Process for the manufacture of triazine derivatives and formulations for oral administration containing triazine derivatives

Abstract

Provided are a method for producing a triazine derivative having a virus proliferation inhibitory action and a formulation for oral administration containing the triazine derivative.

Description

Technical Field

[0001] This invention relates to novel compounds exhibiting coronavirus 3CL protease inhibitory activity, novel synthetic intermediates thereof, or salts thereof, and methods for their manufacture. This invention relates to oral formulations containing triazine derivatives. More specifically, it relates to oral formulations containing a triazine derivative exhibiting inhibitory activity against coronavirus 3CL protease, a pharmaceutically acceptable salt thereof, or a complex thereof as an active ingredient. Background Technology

[0002] Coronaviruses, belonging to the subfamily Coronaviridae of the order Nidovirales, have a genome size of approximately 30 kilobases, making them the largest known single-stranded positive-sense RNA viruses. Coronaviruses are classified into four genera: alpha-coronavirus, beta-coronavirus, gamma-coronavirus, and delta-coronavirus. Of these, two species (HCoV-229E and HCoV-NL63) and five species (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2) are known to infect humans, totaling seven species. Four of these (HCoV-229E, HCoV-NL63, HCoV-HKU1, and HCoV-OC43) are pathogens of the common cold, while the remaining three are Severe Acute Respiratory Syndrome (SARS) coronavirus (SARS-CoV), Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), and the novel coronavirus (SARS-CoV-2), which cause severe pneumonia.

[0003] As the main route of infection for SARS-CoV-2, droplet infection, contact infection, and aerosol infection have been reported. SARS-CoV-2 has been confirmed to remain infective by remaining suspended in the air for approximately 3 hours along with aerosols (Non-Patent Literature 2). The incubation period is approximately 2–14 days, typically presenting with flu-like symptoms such as fever (87.9%), dry cough (67.7%), fatigue (38.1%), and sputum (33.4%) (Non-Patent Literature 3). In severe cases, it has led to acute respiratory distress syndrome, respiratory failure due to acute lung injury, interstitial pneumonia, etc. In addition, multiple organ failure, including renal failure and liver failure, has been reported.

[0004] In Japan, based on drug repositioning of existing drugs, remdesivir as an antiviral drug, dexamethasone as an anti-inflammatory drug, and baricitinib as a rheumatoid arthritis drug were approved as treatments for COVID-19. In January 2022, tocilizumab as an anti-IL-6 receptor antibody was additionally approved. Furthermore, RONAPREVE (Casirivimab / Imdevimab) was exceptionally approved as an antibody cocktail therapy in July 2021, Sotrovimab in September 2021, and molnupiravir in December 2021. However, there is insufficient evidence regarding the efficacy and safety of these drugs. Therefore, the development of treatments for COVID-19 is urgently needed.

[0005] When a coronavirus infects a cell, it synthesizes two polyproteins. These two polyproteins contain a replication complex for producing the viral genome and two proteases. The proteases play an indispensable role in cleaving the viral polyproteins and enabling each protein to function. Of the two proteases, the 3CL protease (the main protease) is responsible for almost all the cleavage of the polyproteins (Non-Patent Literature 4). As a COVID-19 therapeutic targeting the 3CL protease, in June 2021, the Phase 1b trial (NCT04535167) of Lufotrelvir (PF-07304814), conducted by Pfizer, was published on ClinicalTrials.gov. Furthermore, in March 2021, Pfizer announced the commencement of a Phase 1 trial of PF-07321332, a therapeutic for COVID-19. The structural formulas of PF-00835231, Lufotrelvir, and PF-07321332 are shown below, which differ from the chemical structures of the compounds of this invention (Non-Patent Documents 5, 12, and 13, and Patent Documents 6 and 7). PF-00835231:

Chemistry 1

Chemistry 2

Transformation 3

[0006] Non-patent documents 5-8 disclose compounds with 3CL protease inhibitory activity, but none of these documents record or imply compounds, manufacturing methods, or synthetic intermediates related to this invention. Patent documents 1-4 and 8-12 disclose the presence of P2X3 and / or P2X. 2 / 3 Triazine and uracil derivatives with receptor antagonistic effects are available, but none of the literature describes or suggests any inhibitory activity against 3CL protease or antiviral effects. Furthermore, no manufacturing method or synthetic intermediates involved in this invention are described or suggested. Non-patent documents 9-11 disclose triazine derivatives with anti-tumor effects, but none of them describe inhibitory activity against coronavirus 3CL protease or antiviral effects. Furthermore, no compounds, manufacturing methods, or synthetic intermediates associated with this invention are described or implied. Patent document 5 discloses a triazine derivative with glycopeptide receptor regulatory activity, but neither document describes or implies any 3CL protease inhibitory activity or antiviral effect. Furthermore, neither the manufacturing method nor the synthetic intermediates involved in this invention are described or implied. Existing technical documents Patent documents

[0007] Patent Document 1: International Publication No. 2012 / 020749 Patent Document 2: International Publication No. 2013 / 089212 Patent Document 3: International Publication No. 2010 / 092966 Patent Document 4: International Publication No. 2014 / 200078 Patent Document 5: International Publication No. 2012 / 009258 Patent Document 6: International Publication No. 2021 / 205298 Patent Document 7: International Publication No. 2021 / 250648 Patent Document 8: Specification of Chinese Patent Application Publication No. 113620888 Patent Document 9: Specification of Chinese Patent Application Publication No. 113666914 Patent Document 10: Specification of Chinese Patent Application Publication No. 113735838 Patent Document 11: Specification of Chinese Patent Application Publication No. 113773300 Patent Document 12: Specification of Chinese Patent Application Publication No. 113801097 Non-Patent Documents

[0008] Non-Patent Document 1: "COVID-19 Dashboard by the Center for Systems Science and Engineering at Johns Hopkins University", [online], Johns Hopkins University, [retrieved on March 14, 2022], Internet <URL: https: / / coronavirus.jhu.edu / map.html> Non-Patent Document 2: The NEW ENGLAND JOURNAL of MEDICINE (2020), Volume 382, pages 1564-1567 Non-Patent Document 3: "Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)", [online], February 28, 2020, WHO, [retrieved on February 8, 2021], Internet <URL: https: / / www.who.int / docs / default-source / coronaviruse / wh邻china-joint-missio正o正covid-19-final-report.pdf> Non-Patent Document 4: Science (2003), Volume 300, pages 1763-1767 Non-patent literature 5: “A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19”, Journal of Virology, April 26, 2021, [retrieved February 15, 2022], Internet<URL:https: / / journals.asm.org / doi / 10.1128 / JVI.01819-20><doi: 10.1128 / JVI.01819-20> Non-patent literature 6: Cell Research (2020), Volume 30, pp. 678-692 Non-patent literature 7: Science (2020), Volume 368, pp. 409-412 Non-patent literature 8: ACS Central Science (2021), Volume 7, No. 3, pp. 467-475 Non-patent literature 9: Cancer Treatment Reviews (1984), Volume 11, Supplement 1, pp. 99-110 Non-patent literature 10: Contributions to Oncology (1984), Volume 18, pp. 221-234 Non-patent literature 11: Arzneimittel-Forschung (1984), Vol. 11, No. 6, pp. 663-668 Non-Patent Literature 12: 261st Am Chem Soc (ACS) Natl Meet · 2021-04-05 / 2021-04-16 · Virtual, N / A · Abst 243 Non-patent literature 13: Science (2021), Volume 374, pp. 1586-1593 Non-Patent Document 14: "Pfizer's Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk Of Hospitalization Or Death By 89% In Interim Analysis Of Phase 2 / 3 EPIC-HR Study", [online], November 5, 2021, Pfizer Press Release, [Searched February 15, 2022], Internet <URL: https: / / www.pfizer.com / news / press-release / press-release-detail / pfizers-novel-covid-19-oral-antiviral-treatment-candidate> Non-patent document 15: AIMECS 2021 (AFMC International Medicinal Chemistry Symposium 2021), online seminar, November 29 - December 2, 2021. Non-patent literature 16: bioRxiv preprint doi: https: / / doi.org / 10.1101 / 2022.01.26.477782, “Discovery of S-217622, ​​a Non-Covalent Oral SARS-CoV-2 3CLProtease Inhibitor Clinical Candidate for Treating COVID-19” Non-patent literature 17: J. Med. Chem. (2022), Vol. 65, pp. 6499-6512, “Discovery of S-217622, ​​a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19” Summary of the Invention The problem that the invention aims to solve

[0009] The object of this invention is to provide a method for manufacturing a triazine derivative exhibiting coronavirus 3CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a complex thereof. Furthermore, the object of the present invention is to provide an orally administered formulation containing a triazine derivative exhibiting coronavirus 3CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a complex thereof as an active ingredient. means for solving problems

[0010] The present invention relates to the following. (1) A method for producing the compound or its salt represented by formula (III), characterized in that the compound or its salt represented by formula (I) and the compound or its salt represented by formula (II) are reacted in the presence of an acid.

Chemistry 4

Transformation 5

Transformation 6

Transformation 7

Transformation 8

Chemistry 9

Chemistry 10

Chemistry 11

Chemistry 12

Chemistry 13

Chemistry 14

Chemistry 15

Chemistry 16

Chemistry 17

Chemistry 19

Chemistry 20

Chemistry 21

Chemistry 22

Chemistry 23

Chemistry 24

Chemistry 25

Chemistry 26

Chemistry 27

[0011] The compounds manufactured by the manufacturing method involved in this invention have inhibitory activity against coronavirus 3CL protease and are useful as therapeutic and / or preventive agents for coronavirus infection. Furthermore, compounds manufactured by the manufacturing method involved in this invention are useful as pharmaceutical raw materials. Furthermore, pharmaceutical compositions containing fumaric acid cocrystals of compound (I-0005) manufactured by the manufacturing method of the present invention are highly useful as therapeutic agents for COVID-19. The manufacturing method of the present invention is a method capable of producing the compound of the present invention in high yield. The oral formulations (pharmaceutical compositions) of the present invention have inhibitory activity against coronavirus 3CL protease and are useful as therapeutic and / or preventive agents for coronavirus infection. Attached Figure Description

[0012] Figure 1 shows the powder X-ray diffraction pattern of the fumaric acid eutectic of the compound represented by formula (VII) in Example a, in form I (crystal type I). The horizontal axis represents 2θ (°), and the vertical axis represents intensity (count). Figure 2 shows the peak table of the powder X-ray analysis pattern of Figure 1. Figure 3 shows the structure of the asymmetric unit of the fumaric acid eutectic I form (crystal form I) of the compound represented by formula (VII). Figure 4 shows the DSC analysis results of the fumaric acid eutectic I form (crystal form I) of the compound of formula (VII) as shown in Figure 1, which displays the powder X-ray analysis pattern. The horizontal axis represents temperature (°C), and the vertical axis represents heat (W / g). Figure 5 shows the TG / DTA analysis results of the fumaric acid eutectic form I (crystal form I) of the compound represented by formula (VII) as shown in Figure 1, displaying the powder X-ray analysis pattern. The vertical axis represents heat (μV) or weight change (%), and the horizontal axis represents temperature (°C). Cel in the figure refers to degrees Celsius (°C). Figure 6 shows the DVS analysis results of the fumaric acid eutectic of formula (VII) (crystal form I) exhibiting the powder X-ray analysis pattern of Figure 1. No substantial weight change was observed even with changes in humidity, indicating that the crystal is stable to moisture. Figure 7 shows the HPLC determination results of compound I-005 obtained in step 4 of Example 1a. The p% of the compound (compound I-005) represented by formula (VII) is approximately 95 p%. Figure 8 shows the HPLC determination results of compound I-005 obtained in step 4'. The p% of the compound (compound I-005) represented by formula (VII) is approximately 99 p%. Figure 9 shows the powder X-ray diffraction pattern of the fumaric acid eutectic of the compound represented by formula (VII) in Example b, in form I (crystal type I). The horizontal axis represents 2θ (°), and the vertical axis represents intensity (count). Figure 10 shows the peak table of the powder X-ray analysis pattern in Figure 9. Figure 11 shows the structure of the asymmetric unit of the fumaric acid eutectic I (crystal form I) of the compound represented by formula (VII). Figure 12 shows the HPLC results of undried crystals of the compound of formula (VII) obtained in step 5-1 of Example 1b. The p% of the compound of formula (VII) is approximately 99 p%. Figure 13 shows the analytical results for the peak from Figure 12 that excludes the toluene source (RT = approximately 9.8 min). The compound represented by formula (VII) has a pA% of approximately 99.7 pA, and each impurity is less than approximately 0.1 pA. Figure 14 shows the DSC analysis results of the fumaric acid eutectic I form (crystal form I) of the compound of formula (VII) obtained in step 5-2 of Example 1b. Figure 15 shows the TG / DTA analysis results of the fumaric acid eutectic form I (crystal form I) of the compound of formula (VII) obtained in step 5-2 of Example 1b. The weight reduction at 150°C was 0.28%. Figure 16 shows the HPLC results of the fumaric acid cocrystal I form (crystal form I) of the compound of formula (VII) obtained in step 5-2 of Example 1b. Figure 17 shows the particle size distribution of the fumaric acid eutectic of Formula (VII) obtained in step 5-2 of Example 1b, in form I (crystal form I). D50 is 25.35 μm and D90 is 73.56 μm. Figure 18 shows the DVS analysis results of the fumaric acid eutectic I form (crystal form I) of the compound of formula (VII) obtained in step 5-2 of Example 1b. No substantial weight change was observed even with changes in humidity, indicating that the crystal is stable to moisture. Figure 19 shows a comparison of the powder X-ray analysis patterns before and after the DVS determination in Figure 18. The crystal form remains unchanged before and after the DVS determination, indicating that it is stable. Figure 20 shows the powder X-ray diffraction pattern of the toluene derivative of the compound represented by formula (VII). The horizontal axis represents 2θ (°), and the vertical axis represents intensity (count). Figure 21 shows the dissolution behavior of Example 6. The horizontal axis represents time (minutes), and the vertical axis represents the dissolution rate (%). Figure 22 shows the particle size distribution of the active ingredient (fumaric acid co-crystal I-shaped crystal of the compound represented by formula (VII)) used in the formulations of Examples 6A and 6B. Figure 23 shows the particle size distribution of the active ingredient (fumaric acid co-crystal I-shaped crystal of the compound represented by formula (VII)) used in the formulations of Examples 6C and 6D. Figure 24 shows the baseline-based change in SARS-CoV-2 viral titer for Phase 2a. The vertical axis represents the baseline-based change in viral titer (log). 10 (TCID 50 / mL), the horizontal axis shows the evaluation time point. Figure 25 shows the time from initial confirmation to a negative viral titer. The vertical axis represents the proportion of individuals with a negative SARS-CoV-2 viral titer (%). The horizontal axis represents the time from the start of treatment (in hours). Figure 26 shows the baseline change in the total score of the 12 COVID-19 symptoms at each time point. The vertical axis represents the baseline change in the total score of the 12 COVID-19 symptoms. The horizontal axis represents the evaluation time point. Detailed Implementation

[0013] The following explains the meaning of each term used in this specification. Unless otherwise specified, each term shall have the same meaning when used alone or in combination with other terms. The term “composed of” refers to something that only has constituent elements. The term “contains” or “includes” means that it is not limited to the constituent elements and does not exclude elements not recorded. Furthermore, throughout this specification, singular expressions, unless otherwise specified, should be understood to include the concept of their plural forms as well. Therefore, singular articles (such as "a," "an," "the," etc. in English) should be understood to include the concept of their plural forms, unless otherwise specified. Furthermore, unless otherwise specified, the terms used in this specification should be understood to have the meanings commonly used in the aforementioned fields. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meanings as commonly understood by those skilled in the art in which this invention is described. In case of conflict, this specification (including definitions) takes precedence.

[0014] "Halogen" refers to an element containing fluorine, chlorine, bromine, and iodine atoms. Fluorine and chlorine atoms are particularly preferred.

[0015] "Alkyl" refers to a straight-chain or branched hydrocarbon group comprising 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl. Preferred alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Further preferred alkyl groups include methyl, ethyl, n-propyl, isopropyl, and tert-butyl. "C1-C4 alkyl" refers to a straight-chain or branched hydrocarbon group consisting of 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.

[0016] "Aromatic carbocyclic group" refers to a cyclic aromatic hydrocarbon group with one or more rings. Examples include phenyl, naphthyl, anthraceneyl, and phenanthryl. Phenyl is an example of a 6-membered aromatic carbocyclic group. Naphthyl is an example of a 10-membered aromatic carbocyclic group. Anthraciteyl and phenanthryl are examples of 14-membered aromatic carbocyclic groups. Phenyl can be cited as a preferred example of "aromatic carbocyclic group".

[0017] "Aromatic carbide rings" refer to rings derived from the aforementioned "aromatic carbide ring groups".

[0018] "Aromatic heterocyclic group" refers to a monocyclic or two-ring aromatic cyclic group having one or more heteroatoms selected from O, S and N, either the same or different. Aromatic heterocyclic groups with two or more rings also include groups obtained by fusing the rings in the above-mentioned "aromatic carbocyclic groups" onto a monocyclic or aromatic heterocyclic group with two or more rings, wherein the bonding site can be located on any ring. The monocyclic aromatic heterocyclic group is preferably 5- to 8-membered, more preferably 5- or 6-membered. Examples of 5-membered aromatic heterocyclic groups include pyrroloyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. Examples of 6-membered aromatic heterocyclic groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. As a 2-ring aromatic heterocyclic group, it is preferably 8 to 10-membered, more preferably 9-membered or 10-membered. Examples include indolyl, isoindolyl, indazole, inazinyl, quinolinyl, isoquinolinyl, cenolinyl, phthalazinyl, quinazolinyl, naphthidyl, quinoxalinyl, purine, pteridinyl, benzopyrimidinyl, benzoisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, isobenzofuranyl, benzothiophene, benzotriazolyl, imidazopyridyl, triazolpyridyl, imidazothiazolyl, pyrazolpyridazinyl, oxazolpyridyl, thiazopyridyl, etc. Examples of 9-membered aromatic heterocyclic groups include indolyl, isoindolyl, indazole, inazinyl, purine, benzopyrimidinyl, benzoisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzofuranyl, imidazopyridyl, triazolpyridyl, oxazolpyridyl, and thiazopyridyl. Examples of 10-membered aromatic heterocyclic groups include quinolinyl, isoquinolinyl, cenolinyl, phthalazinyl, quinazolinyl, naphthidyl, quinoxalolinyl, pteridinyl, and pyrazolopyridazinyl. As an aromatic heterocyclic group with 3 or more rings, it is preferably 13 to 15 members. Examples include carbazolyl, acridinel, oxanthyl, phenothiazinyl, phenothiazinyl, phenothiazinyl, dibenzofuranyl, etc. Triazole groups are a preferred example of "aromatic heterocyclic groups".

[0019] "Aromatic heterocycles" refer to rings derived from the aforementioned "aromatic heterocycle groups".

[0020] Examples of substituents for "substituted alkyl" include the following group of substituents A. A carbon atom at any position may be bonded to one or more groups selected from the following group of substituents A. Substituent group A: halogen, cyano, and nitro. Examples of substituents that "substitute C1-C4 alkyl groups" include the following group of substituents B. A carbon atom at any position may be bonded to one or more groups selected from the following group of substituents B. Substituent group B: halogen, cyano, and nitro.

[0021] As substituents on the rings of "aromatic carbocyclic groups" and "aromatic heterocyclic groups," such as "substituted aromatic carbocyclic groups" and "substituted aromatic heterocyclic groups," the following substituent group C can be cited. An atom at any position on the ring can be bonded to one or more groups selected from the following substituent group C. Substituent group C: halogen, cyano, nitro and alkyl.

[0022] The compounds shown in formulas (VI) and (VII) are not limited to specific isomers, but include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereomers, optical isomers, rotational isomers, etc.), racemates, or mixtures thereof.

Chemistry 28

Chemistry 29

[0023] Substantively without expression (VII):

Transformation 30

[0024] Furthermore, in the compounds shown by formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), and (XI) (hereinafter referred to as formula (VII), etc.), one or more hydrogen, carbon, and / or other atoms may be replaced by isotopes of hydrogen, carbon, and / or other atoms. Examples of such isotopes include... 2 H, 3 H, 11 C 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F, 123 I and 36 Like Cl, it includes hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine. Compounds represented by formula (VII) also include compounds substituted with such isotopes. Compounds substituted with such isotopes are also useful as pharmaceuticals, including all radiolabeled compounds represented by formula (VII). Furthermore, a "radiolabeling method" for manufacturing such "radiolabeled compounds" is also included in this invention, and such "radiolabeled compounds" are useful as tools for drug metabolism kinetic studies, assays, and / or diagnostics. Furthermore, the crystal of the present invention can be a deuterium transformant. The crystal of the present invention can be isotopized (e.g., 3 H,14 C 35 S, 125 (I, etc.) mark.

[0025] Radiolabeled compounds of formula (VII) and the like can be prepared by methods known in the art. For example, tritium-labeled compounds of formula (VII) and the like can be prepared by introducing tritium into a specific compound of formula (VII) and the like through a dehalogenation reaction using a tritium catalyst. This method involves reacting a precursor of the compound of formula (VII) and the like, which is appropriately halogenated, with tritium gas in the presence or absence of a suitable catalyst, such as Pd / C, and in the presence or absence of a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". 14 C-labeled compounds can be used with... 14 It is prepared from carbon (C) as a raw material.

[0026] In the formulations of the present invention, pharmaceutically acceptable salts of compounds represented by formula (VII) and the like may be used. Pharmaceutically acceptable salts of compounds represented by formula (VII) and the like can be exemplified by salts of compounds represented by formula (VII) with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, methylpyridine, quinoline, etc.) and amino acids, or salts of inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). These salts can be formed by conventional methods. A pharmaceutically acceptable salt of a compound represented by formula (VII), for example, consisting of a compound represented by formula (VII) and a countermolecule or counterion, may contain any number of countermolecules or counterions. A pharmaceutically acceptable salt of a compound represented by formula (VII) is a substance formed via ionic bonds through proton movement between the compound and the countermolecule or counter atom.

[0027] In the formulations of the present invention, complexes of compounds of formula (VII) or pharmaceutically acceptable salts thereof may be used. Compounds of formula (VII) or pharmaceutically acceptable salts thereof sometimes form solvates (e.g., hydrates), cocrystals, and / or inclusion compounds, which are referred to herein as "complexes".

[0028] As used in this specification, "solvent" refers to a compound, such as that of formula (VII), that can be coordinated with any number of solvent molecules (e.g., water molecules). By placing the compound of formula (VII) or its pharmaceutically acceptable salt in the atmosphere, it absorbs moisture, sometimes adsorbs water, and sometimes forms hydrates.

[0029] Examples of solvent molecules include acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methyl cyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydronaphthalene, toluene, 1,1,2-trichloroethylene, xylene, acetic acid, anisole, and 1 -Butanol, 2-Butanol, n-Butyl acetate, tert-Butyl methyl ether, Cumene, Dimethyl sulfoxide, Ethyl acetate, Diethyl ether, Ethyl formate, Formic acid, Heptane, Isobutyl acetate, Isopropyl acetate, Methyl acetate, 3-Methyl-1-butanol, Methyl ethyl ketone, Methyl isobutyl ketone, 2-Methyl-1-propanol, Pentane, 1-Pentanol, 1-Propanol, 2-Propanol, Propyl acetate, Tetrahydrofuran, Water (i.e., hydrate), Ethanol, Acetone, 1,1-Diethoxypropane, 1,1-Dimethoxymethane, 2,2-Dimethoxypropane Isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid and trifluoroacetic acid, preferably acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethyl acetate, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran, etc. Hydrogenated furan, water (i.e., hydrate), ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid and trifluoroacetic acid, more preferably, water (i.e., hydrate), ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid and trifluoroacetic acid, etc.

[0030] As used in this specification, "cocrystal" refers to a regular arrangement of counter molecules within the same crystal lattice, which can contain any number of counter molecules. Furthermore, a cocrystal refers to a non-covalent and non-ionic chemical interaction between the compound and the counter molecules, via hydrogen bonds, van der Waals forces, etc. For example, as a cocrystal of the compound shown in formula (VII), it consists of the compound shown in formula (VII) and a countermolecule, and may contain any number of countermolecules. Preferably, it consists of the compound shown in formula (VII) and fumaric acid, and may contain any number of fumaric acids. More preferably, it is a cocrystal of the compound shown in formula (VII) and fumaric acid in a 1:1 molar ratio. Eutectic phases are distinguished from salt phases by the fact that the compounds are essentially free of charge or neutral. Eutectic crystals are distinguished from hydrates or solvates in that the countermolecules are not in water or solvent.

[0031] The compounds or salts thereof represented by formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), and (XI) of this invention sometimes form solvates (e.g., hydrates), eutectics, and / or polymorphs. This invention also includes various such solvates, eutectics, and polymorphs. A "solvate" can be a compound represented by formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), and (XI) that is coordinated with any number of solvent molecules (e.g., water molecules). Furthermore, polymorphs are sometimes formed by recrystallizing the compounds or salts thereof represented by formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), and (XI).

[0032] As used in this specification, "crystal" refers to a solid composed of atoms, ions, molecules, etc., arranged in a three-dimensional, regular pattern, distinguishing it from amorphous solids that do not have such a regular internal structure. The crystals of this invention can be single crystals, twins, polycrystalline, etc. Furthermore, within a "crystal," there are sometimes "polymorphs" with the same composition but different arrangements within the crystal; these, along with others, are called "crystalline states." In addition, the compounds shown in formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), and (XI) can also be converted into these salts or these pharmaceutically acceptable solvates. The crystals of the present invention can be any of these salts, hydrates, solvates, or polymorphs, and even mixtures of two or more are intended to be included within the scope of the invention. Crystallinity and degree of crystallinity can be determined by a variety of techniques, including, for example, powder X-ray diffraction, Raman spectroscopy, infrared absorption spectroscopy, moisture adsorption-desorption, differential scanning calorimetry, and solubility properties.

[0033] In addition, "polymorphs" are sometimes formed by recrystallizing compounds such as those shown in formula (VII), their pharmaceutically acceptable salts, or complexes thereof. In the formulations of the present invention, various salts, complexes (hydrates, solvates, eutectics, inclusion compounds), polymorphs, and even mixtures of two or more of them can be used.

[0034] (Powder X-ray Diffraction (XRPD)) Powder X-ray diffraction (XRPD) is one of the most sensitive analytical methods for determining the crystalline state and crystallinity of solids. When X-rays are irradiated onto a crystal, they are reflected by the crystal planes and interfere with each other, showing diffraction lines with an ordered pattern corresponding to the periodicity of the structure. On the other hand, for amorphous solids, which typically do not have an ordered repeating periodicity in their structure, no diffraction phenomenon occurs, resulting in characteristic broad XRPD patterns (also known as halo patterns).

[0035] The crystalline state of the compounds shown in formula (VII) can be identified by powder X-ray diffraction patterns and characteristic diffraction peaks. The crystalline state of the compounds shown in formula (VII) can be distinguished from other crystalline states by the presence of characteristic diffraction peaks. The characteristic diffraction peaks used in this specification are peaks selected from the observed diffraction pattern. Preferably, about 10 characteristic diffraction peaks are selected from the diffraction pattern, more preferably about 5, and even more preferably about 3. Based on the differentiation of multiple crystals, peaks identified in one crystal but not in others are considered preferred characteristic peaks for crystal identification, compared to peak intensity. Even one or two such characteristic peaks can characterize the crystal. Comparing the measured graphs, if these characteristic peaks are consistent, it can be said that the powder X-ray diffraction patterns are substantially consistent.

[0036] Generally, the diffraction angle (2θ) in powder X-ray diffraction can have an error range of ±0.2°. Therefore, it should be understood that the value of the diffraction angle in powder X-ray diffraction also includes values ​​within a range of approximately ±0.2°. Thus, this invention includes not only crystals with completely consistent diffraction angles in powder X-ray diffraction, but also crystals with consistent diffraction angles within an error range of approximately ±0.2°.

[0037] The peak intensities shown in the following tables and figures are generally known to vary due to various factors, such as the effect of selective crystal orientation relative to the X-ray beam, the influence of coarse particles, the purity of the analyzed substance, or the crystallinity of the sample. Furthermore, peak positions may also shift based on variations in sample height. Moreover, different shifts are obtained according to Bragg's formula (nλ = 2dsinθ) if different wavelengths are used for measurement, but additional XRPD patterns obtained by using such alternative wavelengths are also included within the scope of this invention.

[0038] (Single crystal structure analysis) One method for identifying crystals is to obtain the crystallographic parameters, further atomic coordinates (values ​​representing the spatial relationships of the atoms), and a three-dimensional structural model. See Toshio Sakurai's "A Guide to X-ray Structure Analysis," published by Shukafusa (1983), and Stout & Jensen's "X-Ray Structure Determination: A Practical Guide," Macmillan Co., New York (1968), etc. Single-crystal structure analysis is useful when identifying the structure of crystals such as complexes, salts, optical isomers, tautomers, and geometric isomers as described in this invention.

[0039] Compounds such as those shown in formula (VII) possess coronavirus 3CL protease inhibitory activity and are therefore useful as therapeutic and / or preventative agents for diseases involving coronavirus 3CL protease. In the case of "therapeutic and / or preventative agents" in this invention, symptom-improving agents are also included. Diseases involving coronavirus 3CL protease include viral infections, and coronavirus infections are preferably cited. As a type of coronavirus, examples of coronaviruses that infect humans include HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. As a means, coronaviruses include alpha coronaviruses and / or beta coronaviruses, more preferably beta coronaviruses, and even more preferably sarbecoviruses. As an example of an alpha coronavirus, HCoV-229E and HCoV-NL63 can be cited. HCoV-229E is particularly preferred. As a type of β-coronavirus, examples include HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. HCoV-OC43 or SARS-CoV-2 are preferred, with SARS-CoV-2 being particularly preferred. As one approach, β-coronaviruses include β-coronavirus lineage A, β-coronavirus lineage B, and β-coronavirus lineage C. β-coronavirus lineage A and β-coronavirus lineage B are more preferred, with β-coronavirus lineage B being particularly preferred. Examples of beta-coronavirus lineage A include HCoV-HKU1 and HCoV-OC43, with HCoV-OC43 being preferred. Examples of beta-coronavirus lineage B include SARS-CoV and SARS-CoV-2, with SARS-CoV-2 being preferred. Examples of beta-coronavirus lineage B include MERS-CoV, which is preferred. As a type of coronavirus, examples include HCoV-229E, HCoV-OC43, and / or SARS-CoV-2, with SARS-CoV-2 being particularly preferred. Examples of coronavirus infections include those caused by HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. Infections caused by HCoV-229E, HCoV-OC43, and / or SARS-CoV-2 are preferred, and infections caused by SARS-CoV-2 are particularly preferred. As a coronavirus infection, novel coronavirus infection (COVID-19) is particularly preferred.

[0040] The manufacturing method involved in this invention will be described below. Step 1: Method for preparing the compound represented by formula (III)

Chemistry 31

[0041] Step 2: Method for preparing the compound shown in formula (VI)

Chemistry 32

[0042] Step 3: Method for preparing the fumaric acid eutectic I form of the compound shown in formula (VII) This step is a method for manufacturing a fumaric acid eutectic I form of the compound represented by formula (VII), characterized in that the compound represented by formula (VII) is crystallized in the presence of fumaric acid, acetone and water. The amount of fumaric acid used is typically 1.0 to 3.0 equivalents, for example 1.0 to 1.5 equivalents, relative to the compound shown in formula (VII). There are no particular restrictions on the crystallization temperature, which can usually be carried out at 40~80℃, preferably at 40~60℃. There is no particular limitation on the crystallization time, but it is usually more than 1 hour, preferably more than 2 hours, and even more preferably 2 to 12 hours. The process can be carried out in the presence of acetone and water, preferably in a ratio of 85:15 to 50:50.

[0043] The compounds represented by formula (VII), pharmaceutically acceptable salts thereof, or complexes thereof (hereinafter referred to as compounds represented by formula (VII), etc.), and compounds manufactured by the manufacturing method involved in the present invention (compounds represented by formula (VII), etc.) have coronavirus 3CL protease inhibitory activity and are therefore useful as treatment and / or prevention agents for viral infections. Furthermore, the compounds manufactured by the manufacturing method of the present invention have medicinal usefulness and preferably have any one or more of the following superior features. a) It has a weak inhibitory effect on CYP enzymes (such as CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.). (b) It exhibits good pharmacokinetics, including high bioavailability and moderate clearance. c) High metabolic stability. d) No irreversible inhibition was observed against CYP enzymes (e.g., CYP3A4) within the concentration range of the assay conditions described in this specification. e) It is not mutagenic. f) Low risk to the cardiovascular system. g) shows high solubility. h) High protein non-binding rate (fu value). i) It has high selectivity for coronavirus 3CL protease. j) It exhibits high coronavirus proliferation inhibitory activity. For example, it exhibits high coronavirus proliferation inhibitory activity when human serum (HS) or human serum albumin (HSA) is added. As a coronavirus replication inhibitor, for example, in the CPE inhibition efficacy confirmation trial (SARS-CoV-2) described later, EC can be cited as an example. 50 The method is to use a concentration of 10 μM or less, preferably 1 μM or less, and more preferably 100 nM or less. Furthermore, the salts, crystals, complexes, and cocrystals of the compounds involved in this invention are useful as medicines, and preferably have one or more of the following excellent features. (bb) indicates high bioavailability, moderate clearance, high AUC, high peak plasma concentration, and good pharmacokinetics. (gg) indicates high solubility, high chemical stability, and low hygroscopicity.

[0044] Pharmaceutical compositions containing compounds of formula (VII) or the like (e.g., compounds manufactured by the manufacturing method according to the present invention) can also be administered by any of the oral or non-oral methods. Examples of non-oral administration include transdermal, subcutaneous, intravenous, intra-arterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ocular, ear, and vaginal administration.

[0045] For oral administration, it can be prepared using conventional methods into any commonly used dosage form, such as solid dosage forms (e.g., tablets, powders, granules, capsules, pills, films, etc.) or liquid dosage forms (e.g., suspensions, emulsions, elixirs, syrups, limonade, alcoholic preparations, aromatic aqueous solutions, extracts, decoctions, tinctures, etc.). Tablets can be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, lozenges, sublingual tablets, lozenges, chewable tablets, or intraorally disintegrating tablets; powders and granules can be dry syrups; and capsules can be soft capsules, microcapsules, or sustained-release capsules.

[0046] In cases where administration is not oral, it may also be administered in any commonly used dosage form, such as injections, drops, or topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalers, lotions, injections, ointments, mouthwashes, enemas, ointments, plasters, gels, creams, patches, mud dressings, powders, suppositories, etc.). Injections may be o / w, w / o, w / w / o, w / o / w emulsions, etc.

[0047] By mixing various pharmaceutical additives such as excipients, binders, disintegrants, and lubricants suitable for the dosage form with an effective amount of the compound shown in formula (VII) (e.g., a compound manufactured by the manufacturing method involved in this invention), a pharmaceutical composition can be prepared. Furthermore, by appropriately changing the effective amount, dosage form, and / or various pharmaceutical additives of the compound of this invention, the pharmaceutical composition can also be prepared for use in children, the elderly, critically ill patients, or for surgery. For example, the pharmaceutical composition for children can be given to newborns (under 4 weeks old), infants (4 weeks to under 1 year old), toddlers (1 year and older but under 7 years old), children (7 years and older but under 15 years old), or patients aged 15 to 18 years. For example, the pharmaceutical composition for the elderly can be given to patients aged 65 years and older.

[0048] The dosage of a pharmaceutical composition containing a compound of formula (VII) or the like (e.g., a compound manufactured by the manufacturing method according to the present invention) (e.g., a pharmaceutical composition containing a compound of formula (VII) in the form of a fumaric acid cocrystal I) is expected to be set based on considerations such as the patient's age, weight, type and severity of disease, and route of administration. In the case of oral administration, it is generally in the range of 0.05 to 200 mg / kg / day, preferably 0.1 to 100 mg / kg / day. In the case of non-oral administration, it varies significantly depending on the route of administration, generally in the range of 0.005 to 200 mg / kg / day, preferably 0.01 to 100 mg / kg / day. It can be divided into one to multiple administrations per day.

[0049] The compounds represented by formula (VII) (e.g., compounds manufactured by the manufacturing method involved in this invention) may be used in combination with, for example, other treatments for COVID-19 (including approved drugs and drugs under development or to be developed in the future) (hereinafter referred to as combination drugs) for the purpose of enhancing the effect of the compound or reducing the dosage of the compound. In this case, the timing of administration of the compound and the combination drug is not limited; they may be administered to the recipient simultaneously or at time intervals. Furthermore, the compound and the combination drug may be administered as two or more formulations containing their respective active ingredients, or as a single formulation containing these active ingredients.

[0050] The dosage of the combined medication can be appropriately selected based on clinically used doses. Furthermore, the ratio of the compound of the present invention to the combined medication can be appropriately selected according to the recipient, route of administration, recipient's disease, symptoms, and combination. For example, when the recipient is a human, 0.01 to 100 parts by weight of the combined medication can be used relative to 1 part by weight of the compound of the present invention.

[0051] A formulation can be prepared by mixing various pharmaceutical additives such as excipients, binders, disintegrants, and lubricants suitable for its dosage form into an effective amount of the compound shown in formula (VII). The formulation of this invention can be administered orally. For oral administration, it can be prepared using conventional methods into any commonly used dosage form, such as solid dosage forms (e.g., tablets, powders, granules, dry syrups, capsules, pills, films, etc.) or liquid dosage forms (e.g., suspensions, emulsions, elixirs, syrups, limonades, alcoholic beverages, aromatic waters, extracts, decoctions, tinctures, etc.). Tablets can be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, lozenges, sublingual tablets, lozenges, chewable tablets, or intraorally disintegrating tablets; powders and granules can be dry syrups; and capsules can be soft capsules, microcapsules, or sustained-release capsules. Preferably, it is an orally administered solid dosage form or suspension, more preferably an orally administered solid dosage form, and particularly preferably tablets or granules.

[0052] The tablet can be any shape, specifically round, oval, spherical, stick-shaped, or donut-shaped. Furthermore, it can be a laminated tablet, a tablet with a core, etc., with single-layer tablets being preferred as they are easy to manufacture. Additionally, symbols, text, etc., for improved legibility can be engraved, and dividing lines can be added.

[0053] Furthermore, the formulations of the present invention can also be used for children, the elderly, critically ill patients, or surgical applications by appropriately modifying the effective amount, dosage form, and / or various pharmaceutical additives of the compounds shown in Formula (VII). For example, the pediatric pharmaceutical composition can be given to newborns (under 4 weeks old), infants (4 weeks to under 1 year old), toddlers (1 year and older but under 7 years old), children (7 years and older but under 15 years old), or patients aged 15 to 18 years. For example, the formulation for the elderly can be given to patients aged 65 years and older.

[0054] The dosage of the formulation of the present invention (e.g., a formulation comprising a cocrystal of fumaric acid in form I containing the compound shown in formula (VII)) is expected to be determined based on considerations such as the patient's age, weight, type and severity of disease, and route of administration. In the case of oral administration, it is typically in the range of 0.05 to 200 mg / kg / day, preferably 0.1 to 100 mg / kg / day. In the case of non-oral administration, it varies significantly depending on the route of administration, typically in the range of 0.005 to 200 mg / kg / day, preferably 0.01 to 100 mg / kg / day. It can be divided into one to multiple administrations per day.

[0055] The amount of the compound represented by formula (VII) contained in the formulation of the present invention is not particularly limited as long as it is in a quantity that is easy for patients to take and can be used for formulation manufacturing, and is 1 to 450 mg, preferably 5 to 350 mg, and more preferably 25 to 250 mg. Specifically, the average weight of one tablet, one capsule, or one container containing the compound represented by formula (VII) is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, or 250 mg. In this case, 25mg refers to a range of 22.5mg to 27.5mg, preferably 23.7mg to 26.3mg; 50mg refers to a range of 45.0mg to 55.0mg, preferably 47.5mg to 52.5mg; 75mg refers to a range of 67.5mg to 82.5mg, preferably 71.2mg to 78.8mg; 100mg refers to a range of 90.0mg to 110.0mg, preferably 95.0mg to 105.0mg; and 125mg refers to a range of 112.5mg to 137.5mg, preferably 118.7mg to 131.3mg. 50mg refers to a range of 135.0mg to 165.0mg, preferably 142.5mg to 157.5mg; 175mg refers to a range of 157.5mg to 192.5mg, preferably 166.2mg to 183.8mg; 200mg refers to a range of 180.0mg to 220.0mg, preferably 190.0mg to 210.0mg; 225mg refers to a range of 202.5mg to 247.5mg, preferably 213.7mg to 236.3mg; and 250mg refers to a range of 225.0mg to 275.0mg, preferably 237.5mg to 262.5mg.

[0056] The compounds shown in Formula (VII) may be used in combination with, for example, other treatments for COVID-19 (including approved drugs and drugs under development or to be developed in the future) for the purpose of enhancing the effect of the compound or reducing the dosage of the compound (hereinafter referred to as combination drugs). In this case, the timing of administration of the compounds shown in Formula (VII) and the combination drugs is not limited; they may be administered to the recipient simultaneously or at time intervals. Furthermore, the compounds shown in Formula (VII) and the combination drugs may be formulated into two or more formulations containing their respective active ingredients for administration, or into a single formulation containing these active ingredients for administration.

[0057] The dosage of the combined medication can be appropriately selected based on clinically used doses. Furthermore, the ratio of the compound shown in Formula (VII) to the combined medication can be appropriately selected based on the recipient, route of administration, recipient's disease, symptoms, and combination. For example, when the recipient is a human, 0.01 to 100 parts by weight of the combined medication can be used relative to 1 part by weight of the compound shown in Formula (VII).

[0058] The formulation of this invention may contain a polymer. The polymer may be a polymer listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Standard for Pharmaceuticals Outside the Pharmacopoeia, the Standard for Pharmaceutical Additives, or the Food Additives Codex. Formulations containing the compound of formula (VII), its pharmaceutically acceptable salt or complexes thereof, and high molecular weight compounds may increase the solubility of the compound of formula (VII) in the formulation.

[0059] Examples of polymers include cellulose-based polymers, acrylic polymers, vinyl polymers, and polysaccharides. Examples of cellulose-based polymers include hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose, butyrate, methyl cellulose (MC), methyl hydroxyethyl cellulose, carboxymethyl ethyl cellulose, ethyl cellulose, crystalline cellulose, microcrystalline cellulose, crystalline cellulose·sodium carboxymethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, powdered cellulose, low-substituted hydroxypropyl cellulose, and mixtures of fumaric acid, stearic acid, polyvinyl acetal diethylamino acetate, and hydroxypropyl methyl cellulose. Examples of acrylic polymers include aminoalkyl acrylate copolymer E, polyvinyl acetal diethylaminoacetate, ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, 2-methyl-5-vinylpyridine methacrylate-methacrylic acid copolymer, dried methacrylic acid copolymer, and dimethylaminoethyl methacrylate-methyl methacrylate copolymer. Examples of vinyl polymers include polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol-methyl methacrylate-acrylic acid copolymer, cross-linked polyvinyl ketone, carboxyvinyl polymers, polyvinyl acetal diethylaminoacetate, and polyvinyl alcohol copolymers. In addition, pullulan can be cited as an example of a polysaccharide. Preferably, it is a cellulose-based polymer, an acrylic polymer, and / or a vinyl polymer, more preferably a cellulose-based polymer, and even more preferably hydroxypropyl methylcellulose.

[0060] Alternatively, a preferred formulation is an oral tablet containing the compound of formula (VII), a pharmaceutically acceptable salt thereof, or a complex thereof as an active ingredient, and a cellulose-based polymer.

[0061] In the formulation of the present invention, one or more additives selected from excipients, binders, disintegrants and lubricants may be used.

[0062] In the formulations of this invention, excipients (and sometimes fillers) may be used. Excipients listed in the Japanese Pharmacopoeia, the Standards for Pharmaceuticals Outside the Japanese Pharmacopoeia, the Standards for Pharmaceutical Additives, or the Codex Alimentarius of Food Additives may be used. Examples of excipients include sugar derivatives, starch derivatives, cellulose derivatives, inorganic excipients, β-cyclodextrin, magnesium stearate, calcium stearate, sucrose fatty acid esters, crosspovidone, soybean lecithin, tragacanth powder, gum arabic, dextran, pullulan, etc. As sugar derivatives, there are sugars and sugar alcohols. Examples of sugars include lactose, white sugar, glucose, fructose, and sucrose. Examples of sugar alcohols include mannitol, sorbitol, erythritol, xylitol, powdered maltose syrup, and maltitol. Examples of starch derivatives include starch, potato starch, corn starch, rice starch, partially α-substituted starch, α-substituted starch, porous starch, sodium carboxymethyl starch, hydroxypropyl starch, and sodium carboxymethyl starch with low degree of substitution. Examples of cellulose derivatives include crystalline cellulose, powdered cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl ethyl cellulose, and low-substituted hydroxypropyl cellulose. Examples of inorganic excipients include silicate derivatives, phosphates, carbonates, sulfates, magnesium oxide, titanium oxide, calcium lactate, synthetic hydrotalcite, talc, kaolin, dried aluminum hydroxide, magnesium oxide, and bentonite. Examples of silicate derivatives include hydrated silica, light anhydrous silica, magnesium aluminate metasilicate, synthetic aluminum silicate, and calcium silicate. Examples of phosphates include anhydrous calcium hydrogen phosphate, calcium monohydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, dipotassium phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, and sodium dihydrogen phosphate. Examples of carbonates include precipitated calcium carbonate, calcium carbonate, and magnesium carbonate. Examples of sulfates include calcium sulfate. These excipients can be used in appropriate proportions in two or more combinations. The excipients in the formulation of the present invention are preferably mannitol and / or croscarmellose sodium.

[0063] In the formulation of this invention, a binder may be used, and such binders may be those listed in the Japanese Pharmacopoeia, the Standards for Pharmaceuticals Outside the Japanese Pharmacopoeia, the Standards for Pharmaceutical Additives, or the Codex Alimentarius for Food Additives. Examples of binders include cellulose-based binders, starch-based binders, vinyl-based binders, polyethers, gum arabic, gum arabic powder, gum arabic powder, alginic acid, sodium alginate, sucrose, gelatin, dextrin, pullulan, tragacanth gum, tragacanth gum powder, xanthan gum, pectin, sodium polyacrylate, agar, phellodendron bark powder, guar gum, light anhydrous silicate, hydrogenated oil, etc.

[0064] Examples of cellulose-based binders include carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (sodium carboxymethyl cellulose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose (MC), crystalline cellulose, microcrystalline cellulose, ethyl cellulose, crystalline cellulose·sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, powdered cellulose, and low-substituted hydroxypropyl cellulose.

[0065] Examples of starch-based binders include starch, α-starch, partially α-starch, potato starch, wheat starch, rice starch, porous starch, corn starch, hydroxypropyl starch, and sodium starch glycolate (sodium carboxymethyl starch).

[0066] Examples of vinyl-based adhesives include polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), carboxyvinyl polymers, and copolyvinylpyrrolidone.

[0067] Examples of polyethers include polyethylene glycol (PEG) 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 1500, PEG 1540, PEG 4000, PEG 6000, PEG 20000, glycerol, polyoxyethylene

[105] polyoxypropylene[5] glycol, propylene glycol, etc.

[0068] These adhesives can be mixed in appropriate proportions to use two or more types. The binder in the formulation of the present invention is preferably hydroxypropyl cellulose (HPC).

[0069] In the formulation of this invention, a disintegrant can be used, which may be a disintegrant listed in the Japanese Pharmacopoeia, the Standards for Pharmaceuticals Outside the Japanese Pharmacopoeia, the Standards for Pharmaceutical Additives, or the Codex Alimentarius Conforma. Examples of disintegrants include cellulose-based disintegrants, starch-based disintegrants, vinyl-based disintegrants, and magnesium aluminosilicate.

[0070] Examples of cellulose-based disintegrants include carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol), crystalline cellulose, and powdered cellulose.

[0071] Examples of starch-based disintegrants include some α-substituted starch, potato starch, corn starch, hydroxypropyl starch, sodium carboxymethyl starch, sodium carboxymethyl starch with low degree of substitution, sodium starch glycolate, α-substituted starch, and starch.

[0072] Examples of vinyl-based disintegrants include cross-pollination ketone and polyvinyl alcohol.

[0073] These disintegrants can be used in combination in appropriate proportions of two or more.

[0074] Among disintegrants, those with extremely high swelling ratios are known as "superdisintegrants." Examples of superdisintegrants include calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, and sodium starch glycolate.

[0075] These superdisintegrants can be used in combination in appropriate proportions of two or more. Furthermore, disintegrants and superdisintegrants can be combined. The preferred disintegrant in the formulation of this invention is croscarmellose sodium.

[0076] The formulation of this invention may contain a lubricant, which may be a lubricant listed in the Japanese Pharmacopoeia, the Standards for Pharmaceuticals Outside the Japanese Pharmacopoeia, the Standards for Pharmaceutical Additives, or the Codex Alimentarius Conforma Sinica. Examples of lubricants include stearic acid and metal stearate salts, inorganic lubricants, hydrophobic lubricants, hydrophilic lubricants, sodium stearyl fumarate, etc.

[0077] Examples of stearic acid and its metal salts include magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, and polyethylene glycol stearate 40.

[0078] Examples of inorganic lubricants include talc, light anhydrous silica, hydrated silica, magnesium carbonate, precipitated calcium carbonate, dried aluminum hydroxide gel, magnesium aluminate metasilicate, magnesium silicate, synthetic aluminum silicate, magnesium oxide, and magnesium sulfate.

[0079] Examples of hydrophobic lubricants include cocoa butter, carnauba wax, glycerol fatty acid esters, hydrogenated oil, white beeswax, hydrogenated soybean oil, beeswax, cetyl alcohol, and sodium lauryl ester.

[0080] Examples of hydrophilic lubricants include sucrose fatty acid esters and polyethylene glycol (PEG).

[0081] These lubricants can be used in appropriate proportions with two or more types. The binder in the formulation of this invention is preferably magnesium stearate.

[0082] The formulation of this invention may contain a flow agent, which may be a flow agent listed in the Japanese Pharmacopoeia, the Standards for Pharmaceuticals Outside the Japanese Pharmacopoeia, the Standards for Pharmaceutical Additives, or the Codex Alimentarius Concerning Food Additives. Examples of flow agents include silica, stearic acid and its metal salts, crystalline cellulose, synthetic aluminum silicate, titanium dioxide, heavy anhydrous silicic acid, magnesium aluminum hydroxide, calcium phosphate, talc, corn starch, magnesium aluminate metasilicate, granulated dicalcium phosphate, calcium silicate, anhydrous dicalcium phosphate, and synthetic hydrotalcite.

[0083] Examples of silica include hydrated silica and light anhydrous silicic acid. Examples of stearic acid and its metal salts include stearic acid, calcium stearate, and magnesium stearate.

[0084] These flow agents can be used in combination in appropriate proportions, with two or more types being used together. The binder in the formulation of this invention is preferably crystalline cellulose.

[0085] In the formulation of this invention, there are no particular limitations on the manufacturing method of the granules. Specifically, it is a method of mixing the active ingredients, disintegrants, excipients and other additives, manufacturing a mixed powder, and then granulating the mixed powder. Preferably, it is a wet granulation method by adding water, water containing a binder and a solvent for granulation, a dry granulation method by compression molding without using water, and a melt granulation method.

[0086] In the formulation of the present invention, there are no particular limitations on the method of manufacturing tablets. Specifically, in order to manufacture granules by the above method, further, a disintegrant and a lubricant are mixed with the granules, and the mixed granules are compressed into tablets using a tableting machine. In the formulations of the present invention, after manufacturing the aforementioned granules and tablets, the granules and tablets are sometimes coated with a coating layer. When forming a coating layer on the granules, a fluidized bed granulation coating machine, a fluidized bed rotary coating machine, or the like can be used. When forming a coating layer on the tablets, a pan coating machine, a ventilated coating machine, or the like can be used. In the coating machine, the coating solution is sprayed onto the granules and tablets while they are being flowed, and then dried to form the coating layer. (Example)

[0087] The present invention will be further described in detail below with examples, reference examples, and experimental examples, but the present invention is not limited thereto.

[0088] In addition, the abbreviations used in this specification have the following meanings. Boc: tert-butoxycarbonyl CDI: Carbonyldiimidazole DBU: 1,8-diazabicyclo[5.4.0]-7-undecene DIEA: N,N-Diisopropylethylamine DMA: N,N-dimethylacetamide DMF: N,N-Dimethylformamide DMSO: Dimethyl sulfoxide DTT: Dithiothreitol EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EDT: 1,2-Ethanedithiol EDTA: Ethylenediaminetetraacetic acid FBS: Fetal bovine serum HOBT: 1-Hydroxybenzotriazole LHMDS: Lithium Bis(trimethylsilyl)amide MEM: Eagle's Minimum Necessary Culture Medium NMP: N-methylpyrrolidone Pd(OAc)2: Palladium acetate TFA: Trifluoroacetic acid TMSCl: Trichloromethylsilane Xantphos: 4,5'-bis(diphenylphosphino)-9,9'-dimethyloxanthracene mM: mmol / L μM: μmol / L nM: nmol / L

[0089] (Example a)

[0090] (Methods for identifying compounds) The NMR analyses obtained in each embodiment were performed at 400 MHz using DMSO-d6 and CDCl3. Furthermore, in cases where NMR data are shown, not all measured peaks are recorded. RT stands for retention time in LC / MS (Liquid Chromatography / Mass Spectrometry), determined under the following conditions. (Measurement condition 1') Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7μm id2.1x50mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid. Gradient: After a linear gradient of 5%-100% solvent [B] for 3.5 minutes, maintain 100% solvent [B] for 0.5 minutes. (Measurement condition 2') Column: Shim-pack XR-ODS (2.2μm, id3.0x50mm) (Shimadzu) Flow rate: 1.6 mL / min UV detection wavelength: 254nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid. Gradient: A linear gradient of 10%-100% solvent [B] was applied over 3 minutes, followed by 0.5 minutes of 100% solvent [B]. It should be noted that in the specification, MS(m / z) refers to the value observed by mass spectrometry.

[0091] (HPLC determination conditions) Column: Xselect CSH Fluoro-Phenyl (3.5μm id4.6x150mm) (Waters) Column temperature: a constant temperature around 40℃ UV detection wavelength: 255nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is acetonitrile for liquid chromatography. Gradient: Maintain 20% solvent [B] for 2 minutes, then perform a linear gradient of 20%-37% solvent [B] for 6 minutes, a linear gradient of 37%-50% solvent [B] for 10 minutes, and a linear gradient of 50%-95% solvent [B] for 2 minutes. Flow rate: 1.0 mL / min Injection volume: 10 μL

[0092] (Determination of powder X-ray diffraction patterns) Powder X-ray diffraction determination of the crystals obtained in each example was performed according to the powder X-ray diffraction method described in the general test method of the Japanese Pharmacopoeia. The determination conditions are shown below. (device) SmartLab manufactured by Rigaku Corporation (Operating Instructions) Measurement method: Reflectance method Wavelength used: CuKα line Tube current: 200mA Tube voltage: 45kV Sample plate: aluminum The incident angle of the X-rays: 2.5° Sampling width: 0.02° Detector: HyPix-3000 (2D detection mode)

[0093] (Determination of differential scanning calorimetry (DSC)) The DSC of the crystals obtained in the examples was determined. Approximately 3 mg of the sample was weighed in an aluminum crucible, flattened, and measured. The measurement conditions are shown below. It should be noted that measurements using differential scanning calorimetry (DSC) may introduce errors within ±2°C. Device: TA Instrument Q1000 / TA Instrument Measurement temperature range: 0℃-295℃ Heating rate: 10℃ / minute Atmosphere: N2 50mL / min

[0094] (Determination of TG / DTA data) Approximately 3 mg of the crystals obtained in the example was weighed and placed in an aluminum crucible for determination in an open system. The determination conditions are as follows. Device: Hitachi Haikou TG / DTA STA7200RV Measurement temperature range: room temperature - 350℃ Heating rate: 10℃ / minute

[0095] (Determination of moisture adsorption-desorption isotherms) Weigh approximately 15–25 mg of the sample into a sample crucible and perform the determination. The determination conditions are shown below. Device: DVS Adventure, manufactured by Surface Measurement Systems Ltd. Measurement points: from 0% RH every 5% to 95% RH, and from 95% RH every 5% to 0% RH. Temperature: 25℃

[0096] (Methods for determining and analyzing single-crystal structures) The determination conditions and analytical methods for single-crystal structure analysis are shown below. (device) Ligaku Corporation XtaLAB P200 MM007 (Measurement conditions) Measurement temperature: 25℃ Wavelength used: CuKα line (λ=1.5418Å) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) (Data Processing) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) The data undergoes Lorentz and polarization correction, as well as absorption correction. (Crystal Structure Analysis) Phase determination was performed using the direct method ShelXT (Sheldrick, GM, 2015), and refinement was performed using ShelXL (Sheldrick, GM, 2015) employing full-matrix least squares. Temperature factors for non-hydrogen atoms were refined anisotropically. Hydrogen atoms were imported from ShelXL using default parameters and treated as riding atoms. All hydrogen atoms were refined using isotropic parameters. The graphs were drawn using PLATON (Spek, 1991) and ORTEP (Johnson, 1976). (Example 1a)

[0097] Synthesis of compound (I-005)

Transformation 33

[0098] Step 2: Synthesis of Compound 19 Compound 18 (1.51 g, 4.04 mmol) and TFA (3.02 mL) were mixed. The reaction solution was stirred at room temperature for 4 hours and allowed to stand overnight. The TFA was removed by vacuum distillation, and toluene was added to the residue for azeotropic reaction. Isopropyl ether was added to the residue, and after resuspending, the residue was filtered to give compound 19 (1.22 g, 3.84 mmol, 95% yield). LC / MS (ESI): m / z = 318, RT = 1.68 min, LC / MS determination conditions 1'

[0099] Step 3: Synthesis of Compound 20 Compound 19 (200 mg, 0.63 mmol), DMF (1.8 mL), potassium carbonate (261 mg, 1.89 mmol), and 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (159 mg, 0.946 mmol) were mixed. The reaction solution was stirred at 60 °C for 2 hours, and a saturated aqueous solution of ammonium chloride was added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and concentrated by filtration. The residue was suspended in a mixed solvent of isopropyl ether, hexane, ethyl acetate, and chloroform and filtered. The residue, DMF (1.8 mL), potassium carbonate (261 mg, 1.89 mmol), and 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (159 mg, 0.946 mmol) were mixed. The reaction solution was stirred at 60 °C for 6 hours, and a saturated aqueous solution of ammonium chloride was added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and concentrated by filtration. The residue was suspended in a mixed solvent of isopropyl ether, hexane, ethyl acetate and chloroform, and filtered to give compound 20 (116 mg, 0.281 mmol, yield 45%). LC / MS (ESI): m / z = 413, RT = 1.84 min, LC / MS determination conditions 1'

[0100] Step 4: Synthesis of compound (I-005) Compound 20 (115 mg, 0.279 mmol), THF (2.30 mL), and 6-chloro-2-methyl-2H-indazole-5-amine (60.8 mg, 0.335 mmol) were mixed. LHMDS (558 μL, 0.558 mmol) was added dropwise to the reaction solution at 0 °C. The reaction solution was stirred at 0 °C for 2.5 h and then at room temperature for 40 min, followed by the addition of a saturated aqueous ammonium chloride solution. The organic layer was extracted with chloroform and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol) to give compound (I-005) (61.8 mg, 0.116 mmol, yield 42%). The HPLC results of compound I-005 are shown in Figure 7. 1 H-NMR(CDCl3) δ: 7.96 (s, 1H), 7.82 (d, J = 2.5Hz, 2H), 7.48 (brs, 1H), 7.45-7.37 (m, 1H), 7.08 (s, 1H), 6.97-6.88 (m, 1H), 5.35 (s,2H), 5.17 (s, 2H), 4.21 (s, 3H), 3.89 (s, 3H). LC / MS (ESI): m / z = 532, RT = 1.70 min, LC / MS measurement conditions 1' (Example 2a)

[0101] 1170 mg of compound (I-005) was added to 278 mg (1.1 eq) of fumaric acid and 5.85 mL of ethyl acetate, and the mixture was stirred at room temperature for 45 minutes. The solid was filtered off and dried to obtain a form I eutectic of fumaric acid of the compound shown in formula (VII) (1369.4 mg, 94.6%).

[0102] The results of single-crystal structure analysis of the fumaric acid eutectic I form of the compound shown in formula (VII) are shown below. R1 (I>2.00s(I)) is 0.0470, and the final difference Fourier transform confirms that there is no missing or misplaced electron density. The crystallographic data are shown in Table 1. Table 1 Here, volume refers to the volume per unit lattice, and Z refers to the number of molecules per unit lattice.

[0103] The structure of the asymmetric unit of the fumaric acid eutectic I of the compound represented by formula (VII) is shown in Figure 3.

[0104] In the asymmetric unit, one molecule each of the compound shown in formula (VII) and fumaric acid exists. No ionic chemical interactions were confirmed; the eutectic was identified as having a 1:1 molar ratio. The bond distance between N10 and C9 is approximately 1.26 Å, and the bond distance between N16 and C9 is approximately 1.37 Å. Based on these bond distances, the compound of formula (VII) in the fumaric acid eutectic form I is identified as having an imino structure.

Transformation 34

[0105] The DSC analysis results of the fumaric acid eutectic I-shaped crystal of the compound of formula (VII), which shows the powder X-ray analysis pattern of Figure 1, are shown in Figure 4. The onset temperature of the endothermic peak is shown to be approximately 272 °C.

[0106] The TG / DTA analysis results of the fumaric acid eutectic I form (crystal form I) of the compound represented by formula (VII) shown in Figure 1 are shown in Figure 5.

[0107] The DVS analysis results of the fumaric acid eutectic I form (crystal form I) of the compound represented by formula (VII) shown in Figure 1 are shown in Figure 6.

[0108] It should be noted that the synthesis of the compound (I-005) shown in formula (VII) can also be carried out as follows. Step 4' In THF (6 mL), LHMDS (1 M in THF; 1.46 mL, 1.46 mmol) was added dropwise to compound 20 (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazole-5-amine (172 mg, 0.946 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2.5 h and at room temperature for 40 min, and saturated ammonium chloride aqueous solution was added. The aqueous layer was extracted with EtOAc. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH, gradient 0-20% MeOH). The resulting solid was cured in acetone / H2O to give compound I-005 (95.3 mg, yield 25%, amber solid). The HPLC determination of compound I-005 is shown in Figure 8 (approximately 99 pA%).

[0109] In addition, the abbreviations used in this specification have the following meanings. BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl CPME: Cyclopentylmethyl ether CbzCl: Benzoic acid chloroformate DME: Dimethyl Ether MEK: Methyl Ethyl Ketone

[0110] (Example b)

[0111] (Methods for identifying compounds) The NMR analyses obtained in each embodiment and reference example were performed at 400 MHz using DMSO-d6 and CDCl3. Furthermore, in cases where NMR data are shown, not all measured peaks may be recorded. "RT" or "retention time" refers to the retention time in LC / MS: liquid chromatography / mass spectrometry or liquid chromatography (HPLC), determined under the following conditions. It should be noted that the MS(m / z) value represents the value observed by mass spectrometry. (Measurement Condition 1) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7μm id2.1x50mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid. Gradient: After a linear gradient of 5%-100% solvent [B] for 3.5 minutes, maintain 100% solvent [B] for 0.5 minutes. (Measurement Condition 2) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7μm id2.1x50mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254nm Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is an acetonitrile solution containing 0.1% formic acid. Gradient: After a linear gradient of 5%-100% solvent [B] for 3.5 minutes, maintain 100% solvent [B] for 0.5 minutes. (Measurement Condition 4) Column: Xselect CSH C18 (3.5μm id 4.6x150mm) (Waters) Column temperature: a constant temperature around 40℃ UV detection wavelength: 254nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is acetonitrile for liquid chromatography. Gradient: After a linear gradient of 5%-95% solvent [B] for 17 minutes, maintain 95% solvent [B] for 3 minutes. Flow rate: 1.0 mL / min Injection volume: 5μL (Measurement Condition 5) Column: Xselect CSH C18 (3.5μm id 4.6x150mm) (Waters) Column temperature: a constant temperature around 40℃ UV detection wavelength: 254nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is acetonitrile for liquid chromatography. Gradient: After a linear gradient of 5%-95% solvent [B] for 17 minutes, maintain 95% solvent [B] for 3 minutes. Flow rate: 1.0 mL / min Injection volume: 10 μL (Measurement Condition 7) Column: Xselect CSH Fluoro-Phenyl (3.5μm id4.6x150mm) (Waters) Column temperature: a constant temperature around 40℃ UV detection wavelength: 255nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is acetonitrile for liquid chromatography. Gradient: Maintain 20% solvent [B] for 6 minutes, then perform a linear gradient of 20%-42% solvent [B] for 21 minutes, then perform a linear gradient of 42%-50% solvent [B] for 4 minutes, and finally perform a linear gradient of 50%-95% solvent [B] for 3 minutes. Flow rate: 1.0 mL / min Injection volume: 10 μL (Measurement Condition 8) Column: Xselect CSH Fluoro-Phenyl (3.5μm id4.6x150mm) (Waters) Column temperature: a constant temperature around 40℃ UV detection wavelength: 255nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is acetonitrile for liquid chromatography. Gradient: Maintain 20% solvent [B] for 2 minutes, then perform a linear gradient of 20%-37% solvent [B] for 6 minutes, a linear gradient of 37%-50% solvent [B] for 10 minutes, and a linear gradient of 50%-95% solvent [B] for 2 minutes. Flow rate: 1.0 mL / min Injection volume: 10 μL (Measurement Condition 9) Column: YMC Jsphere ODS-H80 (4μm id 4.6x250mm) Column temperature: a constant temperature around 40℃ UV detection wavelength: 250nm Mobile phase: [A] is an aqueous solution containing 0.2% trifluoroacetic acid, [B] is methanol for liquid chromatography. Gradient: A linear gradient of 10%-70% solvent [B] was applied for 6 minutes, followed by a 3-minute maintenance of 70% solvent [B]. This was then repeated with a 3-minute linear gradient of 70%-90% solvent, followed by a 5-minute maintenance of 90% solvent [B]. Finally, a 1-minute linear gradient of 90%-95% solvent was applied, followed by a 5-minute maintenance of 95% solvent [B]. Flow rate: 1.0 mL / min Injection volume: 5μL (Measurement Condition 10) Column: Xselect CSH C18 (3.5μm, id 4.6x150mm) Column temperature: a constant temperature around 40℃ UV detection wavelength: 254nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is acetonitrile for liquid chromatography. Gradient: After a linear gradient of 5%-95% solvent [B] for 17 minutes, maintain 95% solvent [B] for 3 minutes. Flow rate: 1.0 mL / min Injection volume: 10 μL (Measurement Condition 11) Column: XBridge C18 (3.5μm, id 4.6x150mm) Column temperature: a constant temperature around 40℃ UV detection wavelength: 210nm Mobile phase: [A] is an aqueous solution containing 10 mM ammonia, [B] is methanol for liquid chromatography. Gradient: Maintain 5% solvent [B] for 5 minutes, perform a linear gradient of 5%-38% solvent [B] for 10 minutes, and perform a linear gradient of 38%-95% solvent [B] for 5 minutes. Flow rate: 0.8 mL / min Injection volume: 10 μL (Measurement Condition 12) Column: C18 column Column temperature: 40℃ UV detection wavelength: 255nm Mobile phase: [A] is an aqueous solution containing 10 mM ammonium formate, [B] is methanol for liquid chromatography. The gradient slowly increased the mixing ratio of mobile phase B from 9:1 to 1:9, and the determination was performed over 28 minutes. Flow rate: 0.3 mL / min Injection volume: 4μL

[0112] (Determination of powder X-ray diffraction patterns) Powder X-ray diffraction (PXRD) measurements of the crystals obtained in each example were performed according to the general test method described in the Japanese Pharmacopoeia. The measurement conditions are shown below. (Apparatus) MiniFlex 600 manufactured by Rigaku Corporation (Operating Instructions) Detector: High-speed one-dimensional detector (D / TecUltra2) Types of light sources: Cu tube bulbs Wavelength used: CuKα line Tube current: 15mA Tube voltage: 40kV Sample plate: Non-reflective sample plate

[0113] (Methods for determining and analyzing single-crystal structures) The determination conditions and analytical methods for single-crystal structure analysis are shown below. (device) Ligaku Corporation XtaLAB P200 MM007 (Measurement conditions) Measurement temperature: 25℃ Wavelength used: CuKα line (λ=1.5418Å) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) (Data Processing) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) The data undergoes Lorentz and polarization correction, as well as absorption correction. (Crystal Structure Analysis) Phase determination was performed using the direct method ShelXT (Sheldrick, GM, 2015), and refinement was performed using ShelXL (Sheldrick, GM, 2015) employing full-matrix least squares. Temperature factors for non-hydrogen atoms were refined anisotropically. Hydrogen atoms were imported from ShelXL using default parameters and treated as riding atoms. All hydrogen atoms were refined using isotropic parameters. The graphs were drawn using PLATON (Spek, 1991) and ORTEP (Johnson, 1976).

[0114] (Determination of differential scanning calorimetry (DSC)) The DSC of the crystals obtained in the examples was determined. Approximately 2 mg of the sample was weighed in an SUS crucible, flattened, and measured. The measurement conditions are shown below. It should be noted that measurements using differential scanning calorimetry (DSC) may introduce errors within ±2°C. Device: DSC 3+ Measurement temperature range: 30℃-300℃ Heating rate: 10℃ / minute Atmosphere: N2 40mL / min

[0115] (Determination of TG / DTA data) Approximately 3 mg of the crystals obtained in the example was weighed and placed in an aluminum crucible for determination in an open system. The determination conditions are as follows. Device: Hitachi Hakashi TG / DTA7200 Measurement temperature range: 30-350℃ Heating rate: 10℃ / minute

[0116] (Determination of moisture adsorption-desorption isotherms) Weigh approximately 15–25 mg of the sample into a sample crucible and perform the determination. The determination conditions are shown below. Device: DVS Adventure, manufactured by Surface Measurement Systems Ltd. Measurement points: from 0% RH every 5% to 95% RH, and from 95% RH every 5% to 0% RH. Temperature: 25℃ It should be noted that the comparison of powder X-ray analysis patterns before and after DVS measurement was determined by the following method. (device) SmartLab manufactured by Rigaku Corporation (Operating Instructions) Measurement method: Reflectance method Wavelength used: CuKα line Tube current: 200mA Tube voltage: 45kV Sample plate: aluminum The incident angle of the X-rays: 2.5° Sampling width: 0.02° Detector: HyPix-3000 (2D detection mode)

[0117] (Determination of particle size distribution) The measurement conditions are as follows. Manufacturer: シンパテック Apparatus: Laser diffraction-type HELOS & RODOS particle size distribution measuring device Range: R4 Distributed pressure: 3 bar Triggering conditions: Concentration ≤ 1% within 2 seconds or actual time 10 seconds. (Example 1b)

[0118] Synthesis of Form I fumaric acid eutectic of the compound shown in formula (VII)

Chemistry 35

[0119] Step 1: Synthesis of Compound 3 Compound 1 (35.0 kg, 238.8 mol, hydrochloride), N,N-dimethylacetamide (273 L), 1,8-diazabicyclo[5,4,0]-7-undecene (87.2 kg, 573.1 mol), and Compound 2 (26.0 kg, 262.7 mol) were mixed and stirred at 25 °C for 10 minutes. N,N'-carbonyldiimidazole (50.3 kg, 310.4 mol) and N,N-dimethylacetamide (7 L) were then added to the reaction solution and stirred at 50 °C for 90 minutes. Methanol (18.4 kg, 573.1 mol) was added to the reaction solution, and the mixture was cooled to 25 °C. The pH was adjusted to 2.5 with 10% sulfuric acid. The slurry was cooled to 5 °C, the solid was filtered off, washed with 20% methanol-water solution, and dried to obtain Compound 3 (38.12 kg, 162.0 mol, yield: 67.9%). HPLC (UV=254nm): RT=8.9min, HPLC determination conditions 4

[0120] Step 2: Synthesis of Compound 5 Compound 3 (34.5 kg, 146.7 mol), acetonitrile (345 L), diisopropylethylamine (26.5 kg, 205.4 mol), and compound 4 (39.6 kg, 176.0 mol) were mixed and stirred at 60 °C for 300 minutes. The reaction solution was cooled to 25 °C, and water (172.5 L) was added. The slurry was cooled to 0 °C, the solid was filtered off, washed with 66% acetonitrile-water solution, and dried to obtain compound 5 (46.10 kg, 121.5 mol, yield: 82.9%). HPLC (UV=254nm): RT=14.7min, HPLC determination conditions 4

[0121] Step 3: Synthesis of Compound 7 Compound 5 (29.0 kg, 76.4 mol), trifluoroacetic acid (72.5 L), and compound 6 (16.5 kg, 152.9 mol) were mixed and stirred at 35 °C for 180 minutes. The reaction solution was cooled, and ethyl acetate (348 L) was added. The mixture was washed with 38% tripotassium phosphate aqueous solution, 2.3% saline solution, and water. The ethyl acetate solution was concentrated to 203 L, and heptane (261 L) was added. The slurry was cooled to 0 °C, the solid was filtered off, washed with a mixed solvent of ethyl acetate and heptane, and dried to give compound 7 (23.60 kg, 65.0 mol, yield: 85.0%). HPLC (UV=254nm): RT=12.5min, HPLC determination conditions 5

[0122] Step 4: Synthesis of Compound 9 Compound 7 (23.3 kg, 64.1 mol), compound 8 (14.0 kg, 83.4 mol, hydrochloride), potassium iodide (6.4 kg, 38.5 mol), cesium carbonate (31.3 kg, 96.2 mol), and N,N-dimethylacetamide (139.8 L) were mixed and stirred at 40 °C for 360 minutes. The reaction solution was cooled to 25 °C, and acetic acid (34.6 kg, 577.2 mol) was added. The insoluble matter was filtered off, and acetonitrile (93.2 L) and water (326.2 L) were added to the filtrate. The slurry was cooled to 0 °C, the solid was filtered off, washed with a 20% acetonitrile aqueous solution, and dried to give compound 9 (20.35 kg, 44.4 mol, yield: 69.2%). HPLC (UV=255nm): RT=25.1min, HPLC determination conditions 7 Repeat steps 1 through 4 twice.

[0123] Step 5-1: Synthesis of Form I fumarate eutectic of the compound shown in formula (VII) Compound 9 (39.0 kg, 80.7 mol), compound 10 (16.2 kg, 84.8 mol), acetic acid (30.7 kg, 484.3 mol), and toluene (234 L) obtained in steps 1-4 were mixed and stirred at 100 °C for 360 minutes. Toluene (390 L) was added, and the resulting slurry was cooled to 25 °C. The solid was filtered off and washed with acetone to obtain undried crystals of the compound shown in formula (VII) (the results of HPLC determination of the undried crystals obtained here under condition 8 are shown in Figures 12 and 13. The peak at RT = 9.8 min is toluene). Step 5-2: Add acetone (613.5 L) and water (109.2 L) to half the amount of the undried crystals of the compound shown in formula (VII), and dissolve at 50 °C. Treat the resulting solution with activated carbon, and add acetone (150.2 L) and water (5.9 L) to the treated solution, concentrating to 702 L. Adjust the temperature of the concentrate to 50 °C, add fumaric acid (4.6 kg, 72.6 mol), acetone (150.2 L), and water (5.9 L), concentrating to 464 L. Add acetone (78 L) to the concentrate, concentrating to 265 L, and add acetone (19.5 L). Adjust the temperature of the slurry to 55 °C and stir for at least 120 minutes. The slurry was cooled to 0°C, the solid was filtered off, washed with acetone, and then dried (the results of DSC, TG / DTA, HPLC, particle size distribution, and DVS determination of the dried crystals obtained here are shown in Figures 14-18. HPLC was performed under determination condition 12. Figure 19 shows a comparison of the powder X-ray analysis patterns before and after the DVS determination). The same operation was repeated for the remaining half, thus obtaining the fumaric acid eutectic I form of the compound shown in formula (VII) (41.68 kg, 64.3 mol, yield: 75.6%). HPLC (UV=255nm): RT=12.8min, HPLC determination conditions 8 (Example 2b)

[0124] Synthesis of the toluene derivative of the compound shown in formula (VII) Step 1 Compound 9 (150 mg, 0.327 mmol) and compound 10 (65.4 mg, 0.360 mmol) were mixed with toluene (1.5 mL) and acetic acid (0.187 mL, 3.27 mmol) and stirred at 100 °C for 9 hours. After cooling to room temperature, heptane (1.5 mL, 10 V) was added and the mixture was filtered. The resulting crystals were washed three times with heptane (0.7 mL). The mixture was dried under reduced pressure to give crystals of the compound represented by formula (VII) (168 mg, 87% yield). The resulting crystals contained 0.5 to 0.6 molecular equivalents of toluene as a solvate, and toluene was not removed under reduced pressure within the normal operating range. A toluene derivative of the compound represented by formula (VII) of good quality was confirmed. 1H-NMR(400MHz, CDCl3) δ ppm: 7.93(s, 1H), 7.70(d, J=2.57Hz, 2H), 7.62(brs,1H), 7.35-7,45(m, 1H), 7.07(m, 1H), 6.92-6.97(td,J=9.63,6.42,1H), 5.34(s, 2H), 5.14(s, 2H), 4.20(s, 3H), 3.87(s, 2H). At 7.14-7.27 ppm and 2.35 ppm, peaks equivalent to 0.5 to 0.6 molecules of toluene were identified.

[0125] See Example 1 for the synthesis of compound S-4.

Transformation 36

[0126] Step 1: Synthesis of compound S-2 Compound S-1 (5.50 kg, 29.5 mol), acetonitrile (21.7 kg), and glacial acetic acid (115.00 kg) were mixed and cooled to 5°C. A 17% sodium nitrite aqueous solution (13.03 kg) was added, and the mixture was stirred for 1 hour. The temperature was then raised to 25°C, and the mixture was stirred for 1.5 hours. The insoluble matter was filtered off and washed with acetonitrile (21.7 kg) and tetrahydrofuran (49.0 kg). Water (460 L) was added to the collected filtrate. The slurry was cooled to 0°C, and the solid was filtered off, washed with water, and dried to obtain compound S-2 (3.75 kg, 19.0 mol, yield: 64.4%). LC / MS (ESI): m / z = 196 (MH), RT = 11.8 min, LC / MS determination conditions 4

[0127] Step 2: Synthesis of compound S-3 Compound S-2 (3.25 kg, 16.4 mol) and ethyl acetate (58.7 kg) were mixed, and trimethyloxonium tetrafluoroborate (2.09 kg, 14.1 mol) was added. The mixture was stirred at 25°C for 7 hours. A mixture of ethyl acetate (29.5 kg) and methanol (10.3 kg) was added to this reaction solution. This mixture was then added to a 5% sodium carbonate aqueous solution (66.3 kg), separating the organic and aqueous layers. The organic layer was washed twice with a 5% sodium chloride aqueous solution (65.8 kg), treated with activated carbon, and concentrated to 42 kg. Tetrahydrofuran (87.0 kg) was added, and the mixture was concentrated to 23 kg. This process was repeated twice, with further addition of tetrahydrofuran (87.0 kg) and concentration to 18.9 kg. The mixture was then heated to 33°C. Heptane (47.0 kg) was added to this mixture. The slurry was cooled to 0°C, the solid was filtered off, washed with a mixture of tetrahydrofuran and heptane, and dried to obtain compound S-3 (1.68 kg, 7.9 mol, yield: 48.2%). LC / MS (ESI): m / z = 212 (M+H), 253 (M+CH3CN+H), RT = 12.4 min, LC / MS determination conditions 4

[0128] Step 3: Synthesis of compound S-4 Compound S-3 (1040 g, 4.9 mol), 10% palladium on carbon (PE type, aqueous) (523 g, 0.25 mol), and ethyl acetate (8.99 kg) were mixed, and hydrazine monohydrate (504 g, 10.1 mol) was added. The mixture was stirred at 35 °C for 3 hours. The 10% palladium on carbon was filtered off and washed with water (1560 g) and ethyl acetate (9.00 kg). 2 mol / L hydrochloric acid (750 g) was added to the collected filtrate to separate the organic and aqueous layers. The aqueous layer was extracted with ethyl acetate (4.69 kg). The organic layers were combined, treated with activated carbon, and concentrated to 11.09 kg. A 4 mol / L hydrogen chloride·ethyl acetate solution (1124 g) was added to the concentrate. The solid was filtered off, washed with ethyl acetate, and dried to obtain compound S-4 (0.84 kg, 3.9 mol, yield: 78.5%). LC / MS (ESI): m / z = 182 (M+H), 223 (M+CH3CN+H), RT = 6.6 min, LC / MS determination conditions 4 Chlorine concentration (ion chromatography): 16.74%

[0129] Synthesis of Compound A-3 (Refer to Example 2)

Chemistry 37

[0130] Step 1: Synthesis of compound A-2 in dichloromethane solution Compound A-1 (9.2 kg, 65.1 mol) and tetrahydrofuran (64 L) were mixed and cooled to 0 °C to prepare a slurry. While maintaining the internal temperature below 8 °C, a Red-AL / tetrahydrofuran solution (65 wt%) of sodium bis(2-methoxy)aluminum (Red-AL) / toluene solution (26.4 kg, 84.9 mol) and tetrahydrofuran (28 L) were added dropwise over 60 minutes. The mixture was then stirred at 0 °C–5 °C for 30 minutes. Acetone (4.9 kg, 84.3 mol) was added dropwise to this reaction solution over 30 minutes, and the temperature was raised to 25 °C. In another reactor, a slurry of sodium potassium tartrate tetrahydrate (46 kg, 163 mol) and tetrahydrofuran (138 L) was prepared, and the reaction solution obtained by quenching the previous Red-AL reduction with acetone was added dropwise over 30 minutes (during which the internal temperature reached approximately 40 °C). After stirring continuously at 40°C for 2 hours, the mixture was cooled to 25°C. Water (2.5 kg) was added and stirred, then filtered. The resulting filtrate was concentrated under reduced pressure to 35 kg (28 L). The filtrate (28 L) was divided into three equal portions. Toluene (2.6 kg) was added to the first portion, and the mixture was concentrated under reduced pressure. This process was repeated eight times until the product was finally concentrated and dried. Dichloromethane (13.5 kg) was added to the concentrated and dried product to prepare a dichloromethane solution of product A-2. The same process was performed on the second and third portions to prepare an A-2 / dichloromethane solution consisting of A-2 (5.53 kg) and dichloromethane (42.7 kg) (yield: 74.8%). 1H-NMR (400MHz, CDCl3, 30℃) δ ppm: 8.00 (s, 1H), 4.74 (s, 2H), 3.90 (s, 3H).

[0131] Step 2: Synthesis of Compound 8 Dichloromethane (44 L) was added to the A-2 / dichloromethane solution prepared in step 1 (containing 5.53 kg of A-2 (48.8 mol) in 49.8 kg of dichloromethane solution), and the temperature was adjusted to 25°C. A mixed solution of thionyl chloride (7.8 kg, 65.5 mol) and dichloromethane (27 L) was added dropwise over 30 minutes, followed by line washing with dichloromethane (8.2 L). After the washing solution was prepared, the mixture was stirred at room temperature for 7 hours. Separately, a 20% sodium acetate aqueous solution (179 kg) was prepared from sodium acetate (36.2 kg, 436 mol) and tap water (143 L). The 20% sodium acetate (119 kg) was added dropwise to the previous reaction solution. The pH at the end of the addition was approximately 4.6. The organic layer obtained in this operation was washed with a 10% sodium chloride aqueous solution prepared from sodium chloride (5.5 kg) and tap water (49 L). The aqueous layer was also extracted with dichloromethane (55 L). The combined organic layers (dichloromethane solution) were concentrated to 33 L, and ethyl acetate (27.5 L) was added for further concentration. After concentration to 33 L, ethyl acetate (47.5 L) was added again, and the mixture was concentrated at atmospheric pressure at a temperature of 60 °C. The resulting inorganic salt was filtered. A hydrochloric acid-ethyl acetate solution (4 mol / L, 12.6 kg) was added to the filtrate for hydrochlorination. The mixture was stirred at 25 °C for 30 minutes and then cooled to around 5 °C. After stirring for 30 minutes and allowing crystallization to mature, the resulting crystal slurry was filtered, washed with cooled ethyl acetate (55 L), and dried under reduced pressure to give compound 8 (5.25 kg) (pale yellow powder, yield: 64.8%). 1H-NMR (400MHz, DMSO-D6, 30℃) δ ppm: 8.54 (s, 1H), 4.70 (s, 2H), 3.86 (s, 3H).

[0132] See Example 3 for the synthesis of compound 10.

Transformation 38

[0133] Step 1: Synthesis of compound B-2 Under a nitrogen atmosphere, compound B-1 (79.1 kg, 499 mol) was added in batches to 395.7 L of 98% sulfuric acid cooled at 0°C–5°C (internal temperature maintained at 0°C–5°C). Potassium nitrate (55.5 kg) was added in 15 batches (at intervals of at least 20 minutes) while maintaining an internal temperature of 0°C–5°C. The mixture was stirred for 5 hours at an internal temperature of 0°C–5°C. The previous reaction solution was then slowly poured into 791 L of water cooled to 0°C–5°C while maintaining an internal temperature of 0°C–5°C. After thorough washing with 39.6 L of 98% sulfuric acid, the mixture was stirred for 5 hours at an internal temperature of 0°C. The slurry was filtered through a centrifuge and washed with 791 L of water. The obtained crude solid was suspended in water (791 L), stirred at 20℃~30℃ for 30 minutes, filtered, washed three times with water (791 L), and dried under reduced pressure to obtain compound B-2 (99.61 kg). 1H-NMR (400MHz, CDCl3) δ ppm: 10.31(s, 1H), 8.46(d, J=6.60Hz, 1H), 7.47(d, J=9.17Hz, 1H). HPLC (UV=250nm): RT=10.9min, HPLC determination conditions 9

[0134] Step 2: Synthesis of compound S-2 Ethanol (697 L), water (697 L), and hydrazine hydrate (73.5 kg, 1468 mol) were mixed and heated to 45 °C. A mixture of compound B-2 (99.6 kg, 489 mol) and ethanol (299 L) was added dropwise over 60 minutes, followed by stirring for 9 hours at 45 °C to 50 °C for 8 hours. While maintaining the internal temperature at 40 °C to 50 °C, an aqueous solution prepared from potassium bicarbonate (53.9 kg, 538 mol) and water (1295 L) was added dropwise over 30 minutes. After cooling to 0 °C to 5 °C and stirring for 1 hour, the mixture was filtered. The solid was washed with a mixture of water (1335 L) and ethanol (657 L) using an aqueous ethanol solution cooled to 0 °C to 5 °C. The mixture was dried under reduced pressure to give compound S-2 (83.25 kg) (yield: 86.9%). 1H-NMR (400MHz, DMSO-d6) δ ppm: 13.56-13.98(m, 1H), 8.67(s, 1H), 8.37(d, J=0.98Hz, 1H), 7.92(d, J=0.61,1H). HPLC (UV=250nm): RT=10.4min, HPLC determination conditions 9

[0135] Step 3: Synthesis of compound S-3 Compound S-2 (84 kg, 430 mol) and ethyl acetate (1596 L) were mixed and stirred at 20-30°C. Trimethyloxonium tetrafluoroborate (77.6 kg, 525 mol) was added in multiple portions, followed by ethyl acetate (84 L), and the mixture was stirred at 25°C for 6 hours. Excess trimethyloxonium tetrafluoroborate was quenched by adding a mixture of methanol (252 L) and ethyl acetate (420 L) dropwise to the previous reaction solution over 2 hours. The quenched reaction solution was then added dropwise to an aqueous sodium carbonate solution (84 kg) and water (1596 L) over 1 hour, followed by ethyl acetate (420 L) and methanol (84 L). The organic layer obtained by separation was washed twice with saturated brine (1680 kg) and filtered through activated carbon. The organic layer was then concentrated under reduced pressure and fed into tetrahydrofuran (2520 L) for further concentration under reduced pressure. After repeating the process of adding tetrahydrofuran and concentrating under reduced pressure, heptane (2139 L) was added dropwise. The mixture was cooled to -5°C to 5°C and then stirred at around 0°C for 1 hour to allow crystallization to mature. The crystallized slurry was filtered and washed with a mixed solution of cooled tetrahydrofuran (224 L) and heptane (912 L). The mixture was then dried under reduced pressure to give compound S-3 (65.73 kg) (yield: 74.1%). 1H-NMR (400MHz, CDCl3) δ ppm: 8.31(s, 1H), 8.13(s, 1H), 7.81(s, 1H), 4.27(s, 3H). HPLC (UV=254nm): RT=10.3min, HPLC determination conditions 10

[0136] Step 4: Synthesis of Compound 10 Compound S-3 (65.7 kg, 310 mol) was mixed with ethyl acetate (657 L), stirred at room temperature, and then cooled to approximately 10 °C for nitrogen purging. 5% platinum-carbon (57.7 kg, containing 53% water) was added. After hydrogen purging, the internal temperature was adjusted to approximately 25 °C while stirring for 4 hours. After confirming the disappearance of the starting material, nitrogen purging was performed, followed by filtration to remove the platinum-carbon catalyst. After liquid-liquid separation, the organic layer was concentrated, and heptane was added dropwise to the ethyl acetate solution to form a crystallization slurry. The slurry was filtered, washed with heptane / ethyl acetate, and dried under reduced pressure to give compound 10 (37.24 kg) (yield: 66.2%). 1H-NMR (400MHz, CDCl3) δ ppm: 7.70(s, 1H), 7.64(s, 1H), 6.89(s, 1H), 4.15(s, 3H). HPLC (UV=254nm): RT=4.8min, HPLC determination conditions 10

[0137] See Example 4 for the synthesis of compound 9.

Chemistry 39

[0138] Step 1: Synthesis of compound C-2 Compound C-1 (10.00 g, 48.0 mmol, methanesulfonate), N,N'-carbonyldiimidazole (8.18 g, 50.4 mmol), acetonitrile (60.00 mL), and diisopropylethylamine (6.83 g, 52.8 mmol) were mixed and stirred at 10 °C for 60 minutes. Compound 1 (8.09 g, 55.2 mmol, hydrochloride) and diisopropylethylamine (7.14 g, 55.2 mmol) were mixed in the reaction mixture and stirred at 50 °C for 210 minutes. The reaction mixture was cooled and concentrated to 45 g. 100 mL of 2-propanol was added, and the mixture was concentrated to 60 g, followed by the addition of another 100 mL of 2-propanol. The slurry was cooled to 0 °C, the solid was filtered off, washed with 2-propanol, and dried to give compound C-2 (10.48 g, 42.2 mmol, yield: 88%). HPLC (UV=210nm): RT=14.5min, HPLC determination conditions 11

[0139] Step 2: Synthesis of compound C-3 Compound C-2 (8.00 g, 32.2 mmol), N,N'-carbonyldiimidazole (6.79 g, 41.9 mmol), tetrahydrofuran (80.0 mL), and 1,8-diazabicyclo[5,4,0]-7-undecene (5.40 g, 35.4 mmol) were mixed and stirred at 25 °C for 120 minutes. Tetrahydrofuran (80.0 mL) was added dropwise, and the reaction mixture was cooled to 0 °C to form a crystallization slurry. The solid was filtered off, washed with tetrahydrofuran, and then heated to dry, thus yielding crystals of compound C-3 (12.6 g, 29.6 mmol, 1,8-diazabicyclo[5,4,0]-7-undecene salt, yield: 92%). HPLC (UV=210nm): RT=1.9min, HPLC determination conditions 11

[0140] Step 3: Synthesis of Compound 9 Compound C-3 (1.00 g, 2.3 mmol, 1,8-diazabicyclo[5.4.0]-7-undecene salt), N,N-dimethylacetamide (5.0 mL), and compound 4 (579.2 mg, 2.6 mmol) were mixed and stirred at 70 °C for 300 minutes. The reaction mixture was cooled, and acetonitrile (10 mL) was added to concentrate the solution to 9.4 g. This process was repeated twice. Compound 6 (461 mg, 4.7 mmol) and diisopropylethylamine (456 mg, 3.5 mmol) were added to the concentrate, and the mixture was stirred at 60 °C for 160 minutes. The reaction mixture was cooled to 25 °C, and acetic acid (703 mg, 11.7 mmol), water (8.0 mL), and seed crystals were added. The resulting crystallization slurry was cooled to 0 °C. Water (12.0 mL) was added to the slurry, the solid was filtered off, washed with 20% acetonitrile aqueous solution, and dried to obtain compound 9 (0.86 g, 1.9 mmol, yield: 79.5%). HPLC (UV=255nm): RT=14.5min, HPLC determination conditions 8

[0141] See Example 5 for the synthesis of compound S-3.

Chemistry 40

[0142] Step 1: Synthesis of compound S-3 Similar to step 1 of Reference Example 3, compound B-2 was obtained. Next, compound B-2 (30 g, 147 mmol) and NMP (120 mL) were mixed, and Boc-carboxylate (56 g, 383 mmol) was added under ice-cold conditions, with stirring at room temperature for 30 minutes. Diisopropylethylamine (38.6 mL, 221 mmol) was added to the reaction mixture, and stirring was carried out at 90 °C for 20 hours. The reaction mixture was set to 80 °C, water (240 mL) was added, and the mixture was cooled to room temperature. The precipitated insoluble matter was filtered off. The resulting solid was washed three times with a mixture of NMP / water = 1 / 2 (15 mL), and further washed three times with water (30 mL). The resulting solid was suspended in isopropyl acetate (60 mL) and heptane (240 mL), stirred at room temperature, and washed three times with isopropyl acetate / heptane = 1 / 4 (30 mL), thereby obtaining compound D-3. The resulting solid was suspended in isopropyl acetate (100 mL). The resulting suspension was added at 55 °C to a mixture of methanesulfonic acid (96 mL, 1474 mmol) and isopropyl acetate (100 mL), and thoroughly washed with isopropyl acetate (60 mL). The mixture was stirred at this temperature for 25 minutes. Under ice-cold conditions, water (240 mL), sodium hydroxide aqueous solution (239 mL, 1916 mmol), and isopropyl acetate (150 mL) were added to the reaction mixture, and the mixture was stirred at 40 °C. Isopropyl acetate (150 mL) was added to the resulting reaction mixture. The resulting organic layer was washed three times with water (90 mL) and concentrated to 45 g. Isopropyl acetate (12 g) and heptane (210 mL) were added, and the resulting insoluble matter was filtered off. The solid was washed three times with isopropyl acetate / heptane = 1 / 7 (30 mL) and dried to obtain compound S-3 (25.3 g, 120 mmol, yield: 81.1%). 1H-NMR (400MHz, CDCl3) δ ppm: 8.34(s, 1H), 8.13(s, 1H), 7.84(s, 1H), 4.28(s, 3H).

[0143] See Example 6 for the synthesis of compound 10.

Chemistry 41

[0144] Step 1: Synthesis of compounds T-2 and T-3 Compound T-1 (40 g, 182 mmol), concentrated sulfuric acid (200 mL, 3677 mmol), and 69% nitric acid (23.3 g, 255 mmol) were mixed under ice-cold conditions and stirred for 3 hours at room temperature, then allowed to stand overnight. The mixture was added to 520 mL of ice water, followed by the addition of dichloromethane (200 mL), and the mixture was separated. The resulting dichloromethane solution was washed twice with 400 mL of 5% sodium bicarbonate aqueous solution and concentrated to dryness. Methanol (120 mL) was added to the resulting solid, and the mixture was concentrated to a volume of 116 g. Methanol was added to the resulting slurry until a volume of 333 g was reached, followed by the addition of water (240 mL). The insoluble matter was filtered off, and the solid was washed with a methanol / water ratio of 1 / 1 (200 mL) and dried to obtain a mixture of compounds T-2 / T-3 = 1 / 2.78 (30.67 g, yield: 58.5%). LC / MS (ESI): As m / z, no MS detection was performed, RT=2.04 min, LC / MS measurement conditions 1

[0145] Step 2: Synthesis of compound T-4 Under a nitrogen atmosphere, 2-propanol (1.4 mL) was added to a mixture (200 mg) of T-2 / T-3 = 1 / 2.78, the mixture was heated to 60 °C, and triethylamine (0.289 mL, 2.07 mmol) was added. The mixture was stirred for 1.5 h. Subsequently, a solution of methylamine hydrochloride (94 mg, 1.39 mmol) dissolved in water (0.4 mL) was added to the reaction mixture at 60 °C, and the mixture was stirred for 3 h. Water (8 mL) was added to the resulting reaction mixture at 60 °C, the mixture was cooled to room temperature, and stirred for 30 min. The precipitated insoluble matter was filtered off, the resulting solid was washed with water (5 mL), and dried to obtain compound T-4 (194 mg, 0.699 mmol, yield: 100%). LC / MS (ESI): m / z = 277 (M+H), RT = 2.46 min, LC / MS determination conditions 2

[0146] Step 3: Synthesis of compound T-5 Compound T-4 (500 mg, 1.80 mmol), 2-propanol (2.5 mL), and tributylphosphine (802 mg, 3.96 mmol) were mixed under a nitrogen atmosphere and stirred at 80 °C for 1.5 hours. After cooling to room temperature, the mixture was concentrated by three solvent displacements with toluene (3 mL) until the concentrated residue reached 5 g. Subsequently, the reaction solution was chilled to 4 °C, and 1.5 mL of 4 mol / L hydrochloric acid-ethyl acetate solution was added, followed by stirring for 20 minutes. The resulting crystallization slurry was filtered, washed with toluene (2.5 mL), and dried to obtain a solid. The obtained solid was gradually added in small amounts to a mixture of water (4.3 mL) and sodium bicarbonate (0.192 g, 2.29 mmol), and the pH was adjusted to 7-8. The mixture was stirred for 30 minutes to obtain a crystallization slurry. The sample was filtered, washed with water (8.6 mL), and dried to obtain compound T-5 (351 mg, 1.43 mmol, yield: 79.4%). LC / MS (ESI): m / z = 245 (M+H), RT = 1.90 min, LC / MS determination conditions 1

[0147] Step 4: Synthesis of Compound 10 Compound T-5 (2.015 g, 8.21 mmol), DME (20 mL), sodium tert-butoxide (1.104 g, 11.49 mmol), benzophenone imine (1.645 mL, 9.80 mmol), BINAP (0.153 g, 0.246 mmol), and palladium diacetoxy (0.036 g, 0.160 mmol) were mixed under a nitrogen atmosphere and stirred at 80 °C for 9 hours, then allowed to stand overnight. Ethanol (10 mL) was added to the resulting suspension, and the mixture was cooled to 5 °C. 30% sulfuric acid (20 mL) was gradually added to the suspension, and the mixture was stirred overnight at room temperature. Ethyl acetate (40 mL) and water (20 mL) were added to the resulting reaction mixture, and the mixture was separated. The aqueous layer was washed with ethyl acetate (10 mL), and the organic layer was washed with 10% sulfuric acid (10 mL). The aqueous layers were combined, cooled, and then neutralized to pH 8 using a 48% sodium hydroxide aqueous solution. Add ethyl acetate (20 mL), filter off the precipitated sodium sulfate, and perform a liquid-liquid extraction. Add ethyl acetate (20 mL) to the resulting aqueous layer and perform a liquid-liquid extraction. Combine the resulting organic layers, concentrate, and further perform solvent displacement four times with ethyl acetate (10 mL). Add heptane (12 mL), and stir the resulting crystallization slurry at ice temperature for 1 hour. Filter, wash with ethyl acetate / heptane = 1 / 3 (6 mL), and dry to obtain compound 10 (1.18 g, 6.5 mmol, yield: 79.2%). LC / MS (ESI): m / z = 182 (M+H), RT = 0.88 min, LC / MS determination conditions 1

[0148] See Example 7 for the synthesis of compound U-4.

Chemistry 42

[0149] Step 1: Synthesis of compound U-2 Compound U-1 (2.09 g, 22.6 mmol, hydrochloride) and CPME (12.04 g) were mixed with water (7 g). A solution of potassium carbonate (4.25 g, 30.8 mmol) dissolved in water (7 g) was slowly added to maintain the reaction temperature at 20–30 °C. The resulting mixture was vigorously stirred, and Cb2Cl (3.50 g, 20.5 mmol) was slowly added to maintain the reaction temperature at 20–30 °C. The mixture was stirred at room temperature for 1 hour. The resulting solution was separated, and the organic layer was washed with water (14 g) and concentrated. CPME (15.05 g) was added to the residue, and the residue was further concentrated to 10.5 g. The resulting solution was heated to 45 °C, and heptane (9.58 g) was added over 30 minutes while maintaining the temperature, followed by stirring for another 30 minutes. After adding heptane (19.15 g), the resulting crystallization slurry was stirred under ice-cold conditions for 30 minutes. The solid was filtered and washed with a mixture of CPME-heptane (3 g - 9.58 g) and dried to obtain compound U-2 (3.41 g, 17.93 mmol, yield: 86%). HPLC (UV=254nm): RT=9.51min, HPLC determination conditions 5

[0150] Step 2: Synthesis of compound U-3 Methanol (31.66 g) was added to compound U-2 (8.00 g, 42.1 mmol), and after cooling to 0 °C, a 28% methanol solution of sodium methoxide (2.43 g, 12.6 mmol) was added, and the mixture was stirred at this temperature for 4 hours. To the resulting solution, a solution of N-methylformylhydrazine (3.74 g, 50.5 mmol) dissolved in methanol (19 g) was added at 0–5 °C, followed by the addition of acetic acid (2.53 g, 42.1 mmol) at this temperature, and the mixture was stirred at 0 °C for 2 hours. The resulting solution was heated to 60 °C and stirred at this temperature for 4 hours. The reaction mixture was concentrated to 32 g, and ethyl acetate (57.73 g) and a 5% sodium bicarbonate aqueous solution (67.53 g) were added. The resulting mixture was stirred for 10 minutes and then separated. The resulting aqueous layer was also extracted with ethyl acetate (57.73 g). The combined organic layers were concentrated to 40 g. MEK (64.4 g) was added, and the solution was further concentrated to 40 g. This process was repeated twice. A solution of methanesulfonic acid (4.04 g, 42.0 mmol) dissolved in MEK (32.2 g) was added to the concentrate at 20–30 °C, and the mixture was stirred for 30 minutes at room temperature. The precipitated crystal slurry was filtered off, and the resulting solid was washed with MEK (25.76 g) and dried to obtain compound U-3 (10.1 g, 29.5 mmol, methanesulfonate, yield: 70%). HPLC (UV=254nm): RT=7.90min, HPLC determination conditions 5

[0151] Step 3: Synthesis of compound C-1 Compound U-3 (10 g, 29.2 mol, methanesulfonate) was mixed with methanol (79.15 g), stirred at room temperature, and then purged with nitrogen. Palladium-carbon (10% palladium, 0.5 g, 5% by weight) was added, purged with hydrogen, and stirred at room temperature for 7 hours. After nitrogen purging, the palladium-carbon catalyst was removed by filtration with diatomaceous earth (registered trademark). The resulting filtrate was concentrated to 50 g. MEK (40.25 g) was added, and the concentration was increased to 40 g. This process was repeated twice. The resulting crystallized slurry was filtered, washed with MEK (25.76 g), and dried to obtain compound C-1 (5.3 g, 25.5 mmol, methanesulfonate, yield: 87%). HPLC (UV=254nm): RT=2.75min, HPLC determination conditions 11

[0152] The results of single-crystal structure analysis of the fumaric acid eutectic I form of the compound shown in formula (VII) are shown below. R1 (I>2.00s(I)) is 0.0470, and the final difference Fourier confirms that there is no accurate or misplaced electron density. The crystallographic data are shown in Table 2. Table 2 Here, volume refers to the volume per unit lattice, and Z refers to the number of molecules per unit lattice.

[0153] Furthermore, the atomic coordinates of non-hydrogen atoms are shown in Tables 3 and 4. Here, U(eq) refers to the equivalent isotropic temperature factor. Table 3 Table 4 .

[0154] Next, the atomic coordinates of the hydrogen atoms are shown in Table 5. Here, U(iso) refers to the isotropic temperature factor. Furthermore, the hydrogen atom numbers in Table 5 are associated with the numbers of the non-hydrogen atoms they are bonded to. Table 5 .

[0155] Furthermore, the interatomic bond distances (unit: angstrom) are shown in Table 6. Table 6 .

[0156] The compound of formula (VII) has a fumaric acid eutectic form I in an asymmetric unit containing one molecule of the compound of formula (VII). The structure of the compound of formula (VII) in the asymmetric unit of the fumaric acid eutectic form I is shown in Figure 11. It should be noted that the numbers of the non-hydrogen atoms in Tables 3-4 and Table 6 correspond to the numbers shown in Figure 11.

[0157] As shown in Table 6, the bond distance for N10-C9 is approximately 1.26 Å, and the bond distance for N16-C9 is approximately 1.37 Å. The bond distance between N10 and C9 (approximately 1.26 Å) is shorter than that between N16 and C9 (approximately 1.37 Å), therefore the compound of formula (VII) in fumaric acid eutectic form I is identified as having an imino structure:

Chemistry 43

[0158] That is, even the same compound may take on an imino structure or an amino structure depending on crystallization conditions, etc. Even when forming salts or complexes, the type of countermolecule in the salt or complex may lead to either an imino structure or an amino structure. Furthermore, even the same countermolecule may take on either an imino structure or an amino structure depending on crystallization conditions, etc. In addition, there are mixtures of compounds with imino structures, their salts, or their complexes with compounds with amino structures, their salts, or their complexes.

[0159] The results of powder X-ray diffraction of the fumaric acid eutectic I-shape of the compound of formula (VII) obtained by the same manufacturing method as step 5-2 of Example 1b are shown. In the powder X-ray diffraction pattern, peaks were identified at diffraction angles (2θ) of 7.7±0.2°, 9.5±0.2°, 10.0±0.2°, 10.9±0.2°, 13.8±0.2°, 14.6±0.2°, 18.6±0.2°, 22.6±0.2°, 23.4±0.2°, and 24.6±0.2°. The powder X-ray diffraction pattern of the fumaric acid eutectic of the compound represented by formula (VII) in form I (crystal type I) is shown in Figure 9. The horizontal axis represents 2θ (°), and the vertical axis represents intensity (count). The peak table in the powder X-ray diffraction pattern of Figure 9 is shown in Figure 10.

[0160] Furthermore, the results of powder X-ray diffraction of the toluene derivative of the compound shown in formula (VII) are presented. In the powder X-ray diffraction pattern, peaks were identified at diffraction angles (2θ): 7.4±0.2°, 8.1±0.2°, 13.7±0.2°, 15.1±0.2°, 16.3±0.2°, 19.3±0.2°, 21.4±0.2°, 22.6±0.2°, 24.6±0.2°, 26.6±0.2°, 27.8±0.2°, and 29.5±0.2°. The powder X-ray diffraction pattern of the toluene derivative of the compound shown in formula (VII) is shown in Figure 20. The horizontal axis represents 2θ (°), and the vertical axis represents intensity (count). For the toluene derivative of the compound shown in formula (VII), the molecular structure (amino form / imino form) was not identified.

[0161] The following describes biological test examples of the compounds of the present invention. The compound represented by formula (VII) involved in this invention has an inhibitory effect on coronavirus 3CL protease, as long as it inhibits coronavirus 3CL protease. Specifically, in the evaluation method described below, IC50 is preferably 50 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less.

[0162] Experiment Example 1: Confirmatory Experiment on the Inhibition of Cytopathic Effect (CPE) Using Human TMPRSS2-Expressed Vero E6 Cells (Vero E6 / TMPRSS2 Cells) <Operating Procedure> • Dilution and dispensing of the test sample The test sample was pre-diluted with DMSO to an appropriate concentration, and a 2-5 times step dilution series was prepared before being dispensed into 384-well plates. • Dilution and injection of cells and SARS-CoV-2 VeroE6 / TMPRSS2 cells (JCRB1819, 5×10⁻⁶) were used. 3 (cells / well) and SARS-CoV-2 (100 TCID) 50 The samples were mixed in medium (MEM, 2% FBS, penicillin-streptomycin) and dispensed into the wells containing the test samples. The samples were then incubated in a CO2 incubator for 3 days. Measurement of dispensing and luminescence signals of CellTiter-Glo (registered trademark) 2.0 After the plates were brought to room temperature after 3 days of incubation, CellTiter-Glo (registered trademark) 2.0 was dispensed into each well and mixed using a plate mixer. After a certain period of time, the luminescence signal (Lum) was measured using a plate reader.

[0163] <Calculation of values ​​for each measured item> • 50% SARS-CoV-2 infection cell death inhibitory concentration (EC50) 50 ) calculate When x is denoted as the logarithm of the compound concentration and y is denoted as the percentage efficacy, the inhibition curve is fitted using the following Logistic regression formula. The value of x when y=50 (%) is calculated as the EC value. 50 . y = min + (max - min) / {1 + (X50 / x) ^Hill} %Efficacy = {(Sample - Virus Control) / (Cell Control - Virus Control)} * 100% Cell control: Average Lum of cell control wells Virus control: Average Lum of virus control wells min: lower limit of the y-axis, max: upper limit of the y-axis, X50: x-coordinate of the inflection point, Hill: slope of the curve at the midpoint between min and max.

[0164] The compounds of the present invention were tested as described above. The results are shown below. Compound I-005: 0.328 μM

[0165] Experimental Example 2: Inhibitory Activity Assay Against SARS-CoV-2 3CL Protease <Materials> Commercially available recombinant SARS-CoV-2 3CL protease Commercially available substrate peptides Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH2 (SEQ ID NO: 1) Internal standard peptides Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln(SEQ ID NO: 2) Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln can be synthesized according to the references (Atherton, E.; Sheppard, RC, "In Solid Phase Peptide Synthesis, A Practical Approach", IRL Press at Oxford University Press, 1989; and Bioorg. Med. Chem., Vol. 5, No. 9, 1997, pp. 1883-1891, etc.). An example is shown below. Using Rink amide resin, H-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Glu(resin)-OαOtBu was synthesized via Fmoc solid-phase synthesis (Lys side chain protected by Boc, Thr side chain protected by tert-butyl, Ser side chain protected by tert-butyl, C-terminal OH of Glu protected by tert-butyl, and the carboxylic acid of the Glu side chain condensed with the resin). N-terminal Dabcyl modification was performed using EDC / HOBT to condense 4-dimethylaminoazobenzene-4'-carboxylic acid (Dabcyl-OH) on the resin. Final deprotection and cleavage from the resin were carried out by treatment with TFA / EDT = 95:5. Subsequently, purification was performed by reversed-phase HPLC. ·RapidFire Cartridge C4 typeA <Operating Procedure> • Preparation of assay buffer In this experiment, an assay buffer consisting of 20 mM Tris-HCl, 100 mM sodium chloride, 1 mM EDTA, 10 mM DTT, and 0.01% BSA was used. (For IC50) 50 For compounds with a value below 10 nM, use an assay buffer consisting of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, and 0.01% BSA. • Dilution and dispensing of the test sample The test sample was pre-diluted with DMSO to an appropriate concentration, and a 2-5 times step dilution series was prepared before being dispensed into 384-well plates. • Addition of enzymes and substrates, enzyme reactions Add 8 μM of substrate and 6 or 0.6 nM of enzyme solution to the prepared compound plate and incubate at room temperature for 3–5 hours. Then, add reaction stop solution (0.067 μM internal standard, 0.1% formic acid, 10 or 25% acetonitrile) to stop the enzyme reaction. • Determination of reaction products Plates after reaction were analyzed using a RapidFire System 360 and mass spectrometer (Agilent, 6550 iFunnel Q-TOF) or a RapidFire System 365 and mass spectrometer (Agilent, 6495C Triple Quadrupole). The mobile phases used for the assay were solution A (75% isopropanol, 15% acetonitrile, 5mM ammonium formate) and solution B (0.01% trifluoroacetic acid, 0.09% formic acid). The reaction products detected by mass spectrometry are recorded as the product area value calculated using RapidFire Integrator or a program capable of equivalent analysis. Additionally, the internal standards detected simultaneously are also calculated and recorded as the internal standard area value. <Calculation of values ​​for each measured item> Calculation of P / IS The area value obtained from the signed project is used to calculate P / IS using the following formula. P / IS = Product area value / Internal standard area value • 50% SARS-CoV-2 3CL protease inhibitory concentration (IC50) 50 ) calculate When x is denoted as the logarithm of the compound concentration and y is denoted as the percentage of inhibition, the inhibition curve is fitted using the following Logistic regression formula. The value of x when y=50 (%) is then calculated as the IC50 value. 50 . y = min + (max - min) / {1 + (X50 / x) ^Hill} %Inhibition = {1 - (Sample - Control(-)) / Control(+) - Control(-))} * 100 Control (-): Average P / IS of wells under enzyme inhibition conditions Control (+): Average P / IS of DMSO control well min: lower limit of the y-axis, max: upper limit of the y-axis, X50: x-coordinate of the inflection point, Hill: slope of the curve at the midpoint between min and max.

[0166] The compounds of the present invention were tested as described above. The results are shown below. Compound I-005: 0.010 μM

[0167] Experimental Examples 1-2: Confirmatory Experiments on the Inhibition of Cytopathic Effect (CPE) by Human TMPRSS2-Expressed Vero E6 Cells (Vero E6 / TMPRSS2 Cells) <Operating Procedure> • Dilution and dispensing of the test sample The test sample was pre-diluted to an appropriate concentration with DMSO, and a 3-fold step dilution series was prepared and dispensed into 96-well plates. • Dilution and injection of cells and SARS-CoV-2 VeroE6 / TMPRSS2 cells (JCRB1819, 1.5 × 10⁶ cells / well) and SARS-CoV-2 hCoV-19 / Japan / TY / WK-521 / 2020, hCoV-19 / Japan / QK002 / 2020, hCoV-19 / Japan / QHN001 / 2020, hCoV-19 / Japan / QHN002 / 2020, hCoV-19 / Japan / TY7-501 / 2021, hCoV-19 / Japan / TY7-503 / 2021, hCoV-19 / Japan / TY8-612 / 2021, hCoV-19 / Japan / TY11-927-P1 / 2021 (30-1000 TCID) were used. 50 The samples were mixed in medium (MEM, 2% FBS, penicillin-streptomycin) and dispensed into the wells containing the test samples. The samples were then incubated in a CO2 incubator for 3 days. Measurement of dispensing and luminescence signals of CellTiter-Glo (registered trademark) 2.0 After the plates were brought to room temperature after 3 days of incubation, CellTiter-Glo (registered trademark) 2.0 was dispensed into each well and mixed using a plate mixer. After a certain period of time, the luminescence signal (Lum) was measured using a plate reader.

[0168] <Calculation of values ​​for each measured item> • 50% SARS-CoV-2 infection cell death inhibitory concentration (EC50) 50 ) calculate When x is denoted as the logarithm of the compound concentration and y is denoted as the percentage efficacy, the inhibition curve is fitted using the following Logistic regression formula. The value of x when y=50 (%) is calculated as the EC value. 50 . y = min + (max - min) / {1 + (X50 / x) ^Hill} %Efficacy = {(Sample - Virus Control) / (Cell Control - Virus Control)} * 100% Cell control: Average Lum of cell control wells Virus control: Average Lum of virus control wells min: lower limit of the y-axis, max: upper limit of the y-axis, X50: x-coordinate of the inflection point, Hill: slope of the curve at the midpoint between min and max.

[0169] The compounds of the present invention were tested as described above. The results are shown below. (SARS-CoV-2 hCoV-19 / Japan / TY / WK-521 / 2020) The fumaric acid eutectic of the compound shown in formula (VII) is in form I: 0.37 μM

[0170] Experimental Example 2-2: Inhibitory Activity Assay Against SARS-CoV-2 3CL Protease <Materials> Commercially available recombinant SARS-CoV-2 3CL protease Commercially available substrate peptides Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH2 (SEQ ID NO: 1) Internal standard peptides Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln(SEQ ID NO: 2) Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln can be synthesized according to the references (Atherton, E.; Sheppard, RC, "In Solid Phase Peptide Synthesis, A Practical Approach", IRL Press at Oxford University Press, 1989; and Bioorg. Med. Chem., Vol. 5, No. 9, 1997, pp. 1883-1891, etc.). An example is shown below. Using Rink amide resin, H-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Glu(resin)-OαOtBu was synthesized via Fmoc solid-phase synthesis (Lys side chain protected by Boc, Thr side chain protected by tert-butyl, Ser side chain protected by tert-butyl, C-terminal OH of Glu protected by tert-butyl, and the carboxylic acid of the Glu side chain condensed with the resin). N-terminal Dabcyl modification was performed using EDC / HOBT to condense 4-dimethylaminoazobenzene-4'-carboxylic acid (Dabcyl-OH) on the resin. Final deprotection and cleavage from the resin were carried out by treatment with TFA / EDT = 95:5. Subsequently, purification was performed by reversed-phase HPLC. ·RapidFire Cartridge C4 typeA <Operating Procedure> • Preparation of assay buffer In this experiment, the assay buffer consisted of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, and 0.01% BSA. • Dilution and dispensing of the test sample The test sample was pre-diluted to an appropriate concentration with DMSO, and a 3-fold step dilution series was prepared and dispensed into 384-well plates. • Addition of enzymes and substrates, enzyme reactions Add 8 μM of substrate and 6 nM of enzyme solution to the prepared compound plate and incubate at room temperature for 3 hours. Then, add reaction stop solution (0.072 μM internal standard, 0.1% formic acid, 10% acetonitrile) to stop the enzyme reaction. • Determination of reaction products The plates after the reaction were analyzed using a RapidFire System 360 and a mass spectrometer (Agilent, 6550 iFunnel Q-TOF). The mobile phases used for the analysis were solution A (75% isopropanol, 15% acetonitrile, 5mM ammonium formate) and solution B (0.01% trifluoroacetic acid, 0.09% formic acid). The reaction products detected by mass spectrometry are recorded as the product area value calculated using RapidFire Integrator. Additionally, the internal standards detected simultaneously are also calculated and recorded as the internal standard area value. <Calculation of values ​​for each measured item> Calculation of P / IS The area value obtained from the signed project is used to calculate P / IS using the following formula. P / IS = Product area value / Internal standard area value • 50% SARS-CoV-2 3CL protease inhibitory concentration (IC50) 50 ) calculate When x is denoted as the logarithm of the compound concentration and y is denoted as the percentage of inhibition, the inhibition curve is fitted using the following Logistic regression formula. The value of x when y=50 (%) is then calculated as the IC50 value. 50 . y = min + (max - min) / {1 + (X50 / x) ^Hill} %Inhibition = {1 - (Sample - Control(-)) / Control(+) - Control(-)) * 100 Control (-): Average P / IS ratio in wells containing neither SARS-CoV-2 3CL protease nor the test substance. Control (+): The average P / IS ratio in wells containing SARS-CoV-2 3CL protease but not the test substance. min: lower limit of the y-axis, max: upper limit of the y-axis, X50: x-coordinate of the inflection point, Hill: slope of the curve at the midpoint between min and max.

[0171] The compounds of the present invention were tested as described above. The results are shown below. The fumaric acid eutectic of the compound shown in formula (VII) is in form I: 0.0132 μM. (Example 5)

[0172] Weigh out fumaric acid eutectic I-shaped crystals of the compound shown in formula (VII) in such a manner that the amount of the compound shown in formula (VII) reaches about 1.8 (w / v)% and add them for dispersion in an aqueous solution containing 0.3 (w / v)% of the polymer. As additives, aminoalkyl methacrylate copolymer E (manufactured by Evonik Corporation), hydroxypropyl cellulose (manufactured by Nippon Soda Corporation), hydroxypropyl methyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), polyvinyl alcohol (manufactured by Merck Corporation), polyvinylpyrrolidone (manufactured by BASF Corporation), and polyvinyl alcohol-methyl methacrylate-acrylic acid copolymer (manufactured by Nisshin Chemical Co., Ltd.) are used. Table 7 .

[0173] Experimental Example 3: Solubility Evaluation 1 mL of each dispersion from Example 5 was added to 14 mL of fasting simulated intestinal fluid (FaSSIF), and stirred at 37°C and 400 rpm for 1 hour using a constant temperature stirrer. After 1 hour of stirring, the sample was filtered through a 0.45 μm filter, and the concentration of the compound represented by formula (VII) in the filtrate was determined by liquid chromatography.

[0174] (Determination method) • Detector: Ultraviolet spectrophotometer (measurement wavelength 222nm) ·Column: ACQUITY UPLC BEH C18 2.1×50mm, 1.7μm • Column temperature: a certain temperature around 40℃ • Mobile phase A: 0.1M ammonium formate solution; Mobile phase B: acetonitrile • Mobile phase delivery: Change the mixing ratio of mobile phase A and mobile phase B to 7:3 or as shown in the table below to control the concentration gradient. Table 8 • Flow rate: Approximately 0.6 mL / min Injection volume: 1 μL or 1.5 μL • Sample coolant temperature: approximately 10°C • Autoinjector cleaning solution: water / methanol mixture (7:3) • Area measurement range: 4 minutes or 7.5 minutes after sample solution injection. Formula (VII) is the formula for calculating the amount of the compound. The amount (%) of the compound represented by formula (VII) = ATII / ΣAT × 100 ATII: Peak area of ​​the compound represented by formula (VII) in the sample solution ΣAT: Total peak area of ​​the sample solution (excluding blank and system peaks)

[0175] (result) The solubility test results of the compound represented by formula (VII) are shown in the table below. The results show that the solubility of the compound represented by formula (VII) is significantly improved by the addition of a polymer. Table 9 The particle size of the fumaric acid eutectic I-type crystal of the compound represented by formula (VII) used in this experiment is D50 of 3.44 μm and D90 of 8.33 μm. (Example 6)

[0176] (Method for manufacturing tablets) To manufacture tablets containing fumaric acid cocrystal I-shaped crystals of the compound shown in formula (VII). The table below shows the formulation of an average of one tablet. The fumaric acid co-crystal I crystals of the compound shown in formula (VII), D-mannitol (manufactured by Roquette), croscarmellose sodium (manufactured by DuPont), hydroxypropyl cellulose (manufactured by Nippon Soda), light anhydrous silica (manufactured by Cabot), and magnesium stearate (manufactured by Mallinckrodt) were sieved through a 30-mesh sieve and then granulated. Granulated and sized granules, crystalline cellulose (manufactured by Asahi Kasei Corporation), magnesium stearate (manufactured by Mallinckrodt Corporation), or light anhydrous silica (manufactured by Cabot Corporation) are added and mixed, and then compressed into tablets with a diameter of 9.0 mm using a static compressor or a rotary tablet press to obtain tablets with the following composition. Table 10 .

[0177] Test Example 4: Dissolution Test of Tablets (Dissolution test method) Dissolution tests were conducted according to Method 2 of the 18th revised Japanese Pharmacopoeia Dissolution Test Method (Dissolution test for surfactants, second solution, paddle method, paddle speed: 50 rpm, result: average value of 2 tablets).

[0178] (Experimental Results) The dissolution test results for Examples 6A, 6B, 6C, and 6D are shown in Figure 21. The results show that rapid dissolution was observed in all examples. The particle size distribution of the active ingredient (formula (VII) fumaric acid co-crystal I-type crystals) used in the formulations of Examples 6A and 6B used in Test Example 4 is shown in Figure 22. 10% of the particles have a diameter of 0.69 μm, 50% have a diameter of 4.00 μm, and 90% have a diameter of 10.80 μm. The particle size distribution of the active ingredient (formula I crystal of fumaric acid co-crystal of the compound represented by formula (VII)) used in the formulations of Examples 6C and 6D used in Test Example 4 is shown in Figure 23. 10% of the particles have a diameter of 0.67 μm, 50% have a diameter of 3.63 μm, and 90% have a diameter of 10.98 μm. The conditions for determining particle size distribution are shown below. Manufacturer: シンパテック Apparatus: Laser diffraction-type HELOS & RODOS particle size distribution measuring device Range: R2 Distributed pressure: 3 bar Triggering conditions: Concentration ≤ 1% within 2 seconds or actual time 10 seconds.

[0179] Example 5: Effect of stabilizers in formulations during time-stability testing The results show the time-dependent stability of the formulation of Example 6A, which is the same batch used in Test Example 4. a. Stability testing method The formulation of Example 6A was either stored in a sealed brown glass bottle at 60°C for two weeks, or in an open brown glass bottle at 40°C and 75% relative humidity for one month. Subsequently, the relevant amounts of the compound represented by formula (VII) in the formulation of this invention were determined. (Sample solution preparation method) (Determination Method) The relevant amounts of the compound represented by formula (VII) in the formulation of this invention were determined by liquid chromatography using the following methods and conditions. • Detector: Ultraviolet spectrophotometer (measurement wavelength: 222nm) • Column: C18 column • Column temperature: a certain temperature around 40℃ • Mobile phase A: 0.01 mol / L ammonium formate solution; Mobile phase B: acetonitrile • The mixing ratio of mobile phase A and mobile phase B was slowly increased from 9:1 to 1:9, and the determination was carried out over 32 minutes. • Flow rate: 0.6 mL / min The total peak area of ​​the chromatogram in the HPLC chart is recorded as 100%, and the percentage (%) relative to its amount is calculated. b. Result The results of the stability tests are shown in the table below. The total relevant mass of the formulation of Example 6A did not increase after being stored in a closed amber glass bottle at 60°C for two weeks, or 2) after being stored in an open amber glass bottle at 40°C and 75% relative humidity for one month, and is therefore stable. Table 11 Based on the above, the formulation of the present invention exhibits high stability against humidity and temperature.

[0180] Trial Example 6: Clinical Trial (Ph2a) The efficacy and safety of repeated oral administration of the investigational drug (active ingredient: fumarate cocrystal I-shaped crystals of the compound represented by formula (VII)) in SARS-CoV-2 infected individuals with only mild / moderate and asymptomatic / mild symptoms were evaluated by a randomized, double-blind comparative trial with placebo as the comparison subject. The primary evaluation metric for Phase 2a Part is common to mild / moderate and asymptomatic SARS-CoV-2 infections: the change in SARS-CoV-2 viral titer at each time point from baseline, confirming the antiviral efficacy of the investigational drug.

[0181] Patients with mild / moderate SARS-CoV-2 infection were selected based on meeting all of the following criteria. (a) Male or female patients aged 12 years or older but under 70 years of age. (b) Diagnosed as positive for SARS-CoV-2 within 120 hours prior to registration. (c) The time from the onset of COVID-19 to registration is within 120 hours. (d) At the time of registration, the individual has one or more of the following symptoms (the 12 symptoms of COVID-19) that are of moderate severity (COVID-19 symptom score: 2 or higher) due to COVID-19 (excluding symptoms that existed before the onset of COVID-19). Systemic symptoms: fatigue, muscle or body aches, headache, chills, fever Respiratory symptoms: runny or stuffy nose, sore throat, cough, wheezing Digestive symptoms: nausea, vomiting, diarrhea

[0182] Asymptomatic SARS-CoV-2 infections were selected from patients who met all of the following criteria. (a) Male or female patients aged 12 years or older but under 70 years of age. (b) Diagnosed as positive for SARS-CoV-2 within 120 hours prior to registration. (c) Asymptomatic: No COVID-19 symptoms (excluding symptoms present before SARS-CoV-2 infection) were confirmed within 2 weeks prior to registration. Systemic symptoms: fatigue, muscle or body aches, headache, chills, fever, abnormal taste, abnormal smell Respiratory symptoms: runny or stuffy nose, sore throat, cough, wheezing Digestive symptoms: nausea, vomiting, diarrhea Asymptomatic / Mild symptoms only: Within 2 weeks prior to randomization, none of the following symptoms (12 symptoms of COVID-19) caused by COVID-19 had a moderate (COVID-19 symptom score: 2) or higher (excluding symptoms present before the onset of COVID-19). Systemic symptoms: fatigue, muscle aches or body aches, headache, chills / sweating, fever or heat. Respiratory symptoms: runny or congested nose, sore throat, cough, wheezing (difficulty breathing) Digestive symptoms: nausea, vomiting, diarrhea

[0183] Methods of drug administration in clinical trials (i) Test drug 250 mg tablet: The tablet contains 250 mg of fumaric acid cocrystal I-form crystals of the compound shown in formula (VII). This 250 mg tablet is prepared by doubling the same components as in Example 6C. 125 mg tablet: The tablet contains 125 mg of fumaric acid cocrystal I-form crystals of the compound shown in formula (VII). This 125 mg tablet is a tablet with the same composition as in Example 6C. (ii) placebo Placebo-D tablets: are tablets indistinguishable in appearance from the above 250 mg tablets, and do not contain the cocrystal I-shaped crystals of fumaric acid of the compound represented by formula (VII). Placebo-B tablets: These are tablets indistinguishable in appearance from the 125 mg tablets described above, and do not contain the cocrystal I-shaped crystals of fumarate of the compound represented by formula (VII).

[0184] Quantity and method of administration In Phase 2a Part, eligible subjects who were diagnosed with mild / moderate or asymptomatic SARS-CoV-2 infection were randomly assigned in a 1:1:1 ratio to receive either the 375 / 125 mg investigational drug, the 750 / 250 mg investigational drug, or a placebo.

[0185] Clinical trial drugs for each group 375 / 125 mg group On day 1, each of the patients was given a 125 mg tablet and a placebo-D tablet. From day 2 to day 5, each patient was given one 125 mg tablet and one placebo-D tablet every day. 750 / 250 mg group On day 1, each of the two patients was given a 250 mg tablet and a placebo-B tablet. From day 2 to day 5, each patient was given one 250 mg tablet and one placebo-B tablet every day. placebo group On day 1, each patient was given a placebo-D tablet and a placebo-B tablet. From day 2 to day 5, each patient was given one placebo-D tablet and one placebo-B tablet every day.

[0186] It should be noted that "Day 1" refers to the first day of the grant, and "Day 2 to Day 5" refers to the second to fifth days from the first day of the grant.

[0187] Key evaluation criteria for effectiveness (Phase 2a Part) The primary evaluation criterion for the effectiveness of Phase 2a Part is common to mild / moderate and asymptomatic SARS-CoV-2 infections: the change in SARS-CoV-2 viral titer at each time point from baseline. This is defined as the absolute change in observed SARS-CoV-2 viral titer at each time point from baseline.

[0188] Analysis of key evaluation items (Phase 2a Part) For each of the mild / moderate SARS-CoV-2 infected individuals, the asymptomatic SARS-CoV-2 infected individuals, and their combined groups, using the mITT population as the subject, a summary statistic of the change in SARS-CoV-2 viral titer from baseline was calculated at each time point. Furthermore, for the combined mild / moderate and asymptomatic SARS-CoV-2 infected individuals, the van Elteren test was applied, comparing SARS-CoV-2 viral titers at each time point at a 5% significance level between the test drug dosage group and the placebo group. The van Elteren test used strata representing the mild / moderate SARS-CoV-2 infected individuals and the asymptomatic SARS-CoV-2 infected individuals.

[0189] The main evaluation results (1) Changes in SARS-CoV-2 viral titers at different time points from baseline (Phase 2a Part) In Phase 2a Part, 69 patients were randomized: 22 were assigned to the 375 / 125 mg group (1 of whom was untreated), 23 to the 750 / 250 mg group, and 24 to the placebo group. Of the 69 patients, 44 had positive RT-PCR results at baseline, and 40 of these had detectable viral titers at baseline. These 40 patients were comprised of 14 in the 375 / 125 mg group, 13 in the 750 / 250 mg group, and 13 in the placebo group. It should be noted that the number and composition of these groups are based on RT-PCR and viral titer assays available up to January 17, 2022. As the final result of Phase 2a Part, among the 69 cases, 47 were positive for baseline RT-PCR, and 43 of these cases had detectable viral titers at baseline. These 43 cases were distributed as follows: 15 in the 375 / 125 mg group, 14 in the 750 / 250 mg group, and 14 in the placebo group.

[0190] The admission date specified in the clinical trial protocol is represented by follow-up, and the correspondence and allowable width between it and the dosing day are as follows. Op V refers to optional follow-up, indicating an optional admission date. Table 12 .

[0191] Figure 24 shows the shift in the mean change in SARS-CoV-2 viral titer from baseline across groups for the modified intention-to-treat population (all subjects randomized and with positive baseline RT-PCR and viral titers). This analysis included mild / moderate SARS-CoV-2 infections and asymptomatic SARS-CoV-2 infections, representing follow-up only on the necessary hospital admission date. Furthermore, viral titers below the detection limit (0.8 log...) were considered. 10 (TCID 50 In the case of / mL), its viral titer value is taken as 0.8 log 10 (TCID 50 / mL). At follow-up 3 (day 4 after dosing) in the 375 / 125 mg group, and at follow-up 2 (day 2 after dosing) and follow-up 3 (day 4 after dosing) in the 750 / 250 mg group, the viral titer was statistically significantly reduced compared to the placebo group at a significance level of 0.05. It should be noted that, in RT-PCR and viral titer assays available up to January 17, 2022, the viral titer also tended to be reduced compared to the placebo group at all time points after follow-up 3 (day 4 after dosing) in the 375 / 125 mg group and after follow-up 2 (day 2 after dosing) in the 750 / 250 mg group.

[0192] In addition, the proportion of positive patients at each time point based on viral titer is shown below. At day 4, the proportion of positive individuals with a viral titer of 0.8 or higher relative to the placebo group decreased by 80% in the 750 / 250mg group and by 63% in the 375 / 125mg group. At day 6, the proportion of positive individuals with a viral titer of 0.8 or higher relative to the placebo group decreased by 54% in the 750 / 250mg group and by 100% in the 375 / 125mg group. At days 4 and 6, both the 750 / 250 mg and 375 / 125 mg groups showed a tendency for a lower proportion of patients with positive viral titers compared to the placebo group. This suggests that the pharmaceutical composition of the present invention can rapidly reduce the number of patients shedding infectious viruses.

[0193] Results of secondary evaluation items (1) Time until the initial confirmation of a negative viral titer (Phase 2a Part) The time until the initial confirmation of a negative viral titer for SARS-CoV-2 is shown in Table 13 and Figure 25 below. Of the 69 patients in Phase 2a Part, 15 were in the 375 / 125 mg group, 13 were in the 750 / 250 mg group, and 14 were in the placebo group. Table 13 [In the stratified log-rank test, only the subject stratum (mild / moderate, asymptomatic / mild) is recorded as the stratification factor.] As shown in Table 13, in the 375 / 125mg group, the median time was as short as 49.8 hours compared to the placebo group, and no significant difference was observed in the time until the initial confirmation of a negative viral titer (p=0.0159). In the 750 / 250mg group, the median time was as short as 48.4 hours compared to the placebo group, and no significant difference was observed in the time until the initial confirmation of a negative viral titer (p=0.0205). Furthermore, as shown in Figure 25, in the placebo group, it took approximately 4.6 days after the start of treatment for 50% of patients to achieve a negative viral titer. In contrast, in the 750 / 250 mg and 375 / 125 mg groups, it took approximately 2.6 days after the start of treatment for 50% of patients to achieve a negative viral titer. Therefore, the time to initially confirming a viral titer in 50% of patients was shortened by approximately 2 days.

[0194] (2) Changes in the total score of the 12 symptoms of COVID-19 at each time point from baseline (Phase 2a Part) The changes in the total score of the 12 symptoms of COVID-19 at each time point from baseline are shown in Figure 6. Of the 69 cases in Phase 2a Part, the results were shown in 13 cases in the 375 / 125 mg group, 12 cases in the 750 / 250 mg group, and 14 cases in the placebo group, which were subjects with mild / moderate symptoms. As shown in Figure 26, in the 375 / 125 mg and 750 / 250 mg groups, at all time points after day 2 (after the first dose), there was a tendency for numerical improvement in the total score of the 12 symptoms of COVID-19 compared with the placebo group.

[0195] (3) Severe illness suppression effect (Phase 2a Part) Of the 69 cases in Phase 2a Part, the proportion of subjects with mild / moderate symptoms whose scores on the ordinal scale (an 8-stage classification of clinical severity, Table 14) first deteriorated to 3 or higher at any point after the start of the phase is shown in Table 15. Table 14 Table 15 As shown in Table 15, no cases were identified in the 375 / 125 mg group and the 750 / 250 mg group where the first deterioration of the ordinal scale to 3 or higher was observed after administration.

[0196] Frequency of harmful incidents In Phase 2a Part, there are no harmful events that result in death, critical illness, or that lead to termination.

[0197] The formulation examples shown below are for illustrative purposes only and are not intended to limit the scope of the invention in any way. The compounds of the present invention can be administered as pharmaceutical compositions via any conventional route, particularly via the intestines, for example, or orally, in the form of tablets or capsules, or non-oral, for example, in the form of injections or suspensions, topically, for example, in the form of lotions, gels, ointments, or creams, or in the form of nasal suppositories. Pharmaceutical compositions comprising the compounds of the present invention in their free or pharmaceutically acceptable salt form, together with at least one pharmaceutically acceptable carrier or diluent, can be manufactured by conventional methods using mixing, granulation, or coating. For example, as oral compositions, they can be tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc., rectally. Furthermore, as injectable compositions, they can be formulated as solutions or suspensions, and can be sterilized; additionally, they can contain preservatives, stabilizers, buffers, etc. (Formulation Example 1) Suspension A suspension is prepared by adding, for example, water for injection to the original drug of the compound shown in formula (VII). (Formulation Example 2) Tablets In the original drug of the compound shown in formula (VII), as an additive, for example D-mannitol or magnesium stearate is added to form tablets. Industrial applicability

[0198] Compounds manufactured by the method of this invention exhibit inhibitory activity against coronavirus 3CL protease and are therefore considered useful as therapeutic and / or preventative agents for diseases or conditions involving coronavirus 3CL protease. The novel synthetic intermediates or their salts, and the manufacturing method of this invention, are useful for pharmaceutical manufacturing. The formulation of the present invention has an inhibitory effect on coronavirus 3CL protease and can be considered useful as a therapeutic and / or preventive agent for diseases or conditions in which coronavirus 3CL protease is involved.

Claims

1. Orally administered solid dosage forms containing formula (VII): 【Chemistry 1】 The compound shown, its pharmaceutically acceptable salt, or complexes thereof are used as active ingredients, and the oral solid dosage form further contains a polymer, wherein the oral solid dosage form is a tablet or granule.

2. The oral solid dosage form according to claim 1, wherein, The active ingredient is a complex of compounds represented by formula (VII), which is a complex containing fumaric acid.

3. The oral solid dosage form according to claim 2, wherein, The complex is a eutectic of the compound shown in formula (VII) and fumaric acid in a 1:1 molar ratio.

4. The oral solid dosage form according to any one of claims 1 to 3, wherein, The polymer is selected from one or more of the following: cellulose polymers, acrylic polymers, and vinyl polymers.

5. The oral solid dosage form according to claim 1, wherein, The formulation contains 125 mg of the compound represented by formula (VII) as the active ingredient.

6. The oral solid dosage form according to claim 5, wherein, The formulation comprises 152.3 mg of a compound of formula (VII) and fumaric acid in a 1:1 molar ratio.

7. The oral solid dosage form according to claim 4, wherein, The polymer is a cellulose-based polymer.

8. The oral solid dosage form according to claim 7, wherein, The cellulose polymer is hydroxypropyl cellulose.

9. The oral solid dosage form according to claim 8, comprising one or more selected from D-mannitol, croscarmellose sodium, light anhydrous silica, crystalline cellulose and magnesium stearate.

10. The oral solid dosage form according to claim 8, comprising D-mannitol, croscarmellose sodium, light anhydrous silica, crystalline cellulose and magnesium stearate.

Images